BRCA1 and BRCA2 as molecular targets for = phytochemicals indole-3-carbinol and genistein in breast and prostate = cancer cells

From: Subject: BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells Date: Mon, 13 Feb 2006 11:40:51 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C63092.57902220" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2180 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C63092.57902220 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nature.com/bjc/journal/v94/n3/full/6602935a.html BRCA1 and BRCA2 as molecular targets for = phytochemicals indole-3-carbinol and genistein in breast and prostate = cancer cells

= = =20 =20 =

advanced=20 search

help

site=20 index

13 February=20 2006

	Journal

		Home
		Current=20 issue
		Previous issue
		Advance=20 Online Publication
		Archive
		Author=20 index
		Keyword=20 index
		Aims &=20 scope
		Editors & = editorial=20 board
		Contacts


	For authors

		Submitting to = BJC
		Copyright=20 agreement


	Services

		Receive=20 Table of Contents by email
		Online = sample=20 copy FREE
		Order sample copy
		Recommend to your library
		Prices
		Indexed=20 in
		Reprints = &=20 permissions
		For=20 advertisers
		Press=20 releases
		About=20 nature publishing group

Translational Therapeutics

British Journal of Cancer (2006) = 94,=20 407-426.
doi:10.1038/sj.bjc.6602935 = Published=20 online 24 January 2006

BRCA1 and=20 BRCA2 as molecular targets for phytochemicals indole-3-carbinol = and=20 genistein in breast and prostate cancer cells

S Fan¹, Q Meng¹, K=20 Auborn², T Carter² and E M=20 Rosen¹

¹Department of Oncology, Lombardi = Comprehensive=20 Cancer Center, Georgetown University, 3970 Reservoir Road, NW, = Washington,=20 DC 20057-1469, USA

²Department of Otolaryngology, North = Shore-Long=20 Island Jewish Research Institute, BoasMarks Biomedical Science = Research=20 Center, 350 Community Drive, Manhasset, New York 11030,=20 USA

3D""=20

Correspondence to: Dr EM Rosen, E-mail: emr36@georgetown.edu

Revi= sed=20 30 November 2005; accepted 30 November 2005; published online 24 = January=20 2006

3D""=20

Indole-3-carbinol = (I3C) and=20 genistein are naturally occurring chemicals derived from = cruciferous=20 vegetables and soy, respectively, with potential cancer prevention = activity for hormone-responsive tumours (e.g., breast and prostate = cancers). Previously, we showed that I3C induces BRCA1 expression = and that=20 both I3C and BRCA1 inhibit oestrogen (E2)-stimulated oestrogen = receptor=20 (ER-) activity in human breast cancer = cells. We now=20 report that both I3C and genistein induce the expression of both = breast=20 cancer susceptibility genes (BRCA1 and BRCA2) in breast (MCF-7 and = T47D)=20 and prostate (DU-145 and LNCaP) cancer cell types, in a time- and=20 dose-dependent fashion. Induction of the BRCA genes occurred at = low doses=20 of I3C (20 M) and genistein = (0.5-1.0 M), suggesting = potential=20 relevance to cancer prevention. A combination of I3C and genistein = gave=20 greater than expected induction of BRCA expression. Studies using = small=20 interfering RNAs (siRNAs) and BRCA expression vectors suggest that = the=20 phytochemical induction of BRCA2 is due, in part, to BRCA1. = Functional=20 studies suggest that I3C-mediated cytoxicity is, in part, = dependent upon=20 BRCA1 and BRCA2. Inhibition of E2-stimulated ER- activity by I3C and genistein was = dependent=20 upon BRCA1; and inhibition of ligand-inducible androgen receptor = (AR)=20 activity by I3C and genistein was partially reversed by = BRCA1-siRNA.=20 Finally, we provide evidence suggesting that the phytochemical = induction=20 of BRCA1 expression is due, in part, to endoplasmic reticulum = stress=20 response signalling. These findings suggest that the BRCA genes = are=20 molecular targets for some of the activities of I3C and=20 genistein.

Keywords:=20 indole-3-carbinol (I3C); genistein; chemoprevention; BRCA1; BRCA2; = EMR;=20 endoplasmic reticulum stress response

3D""=20

Indole-3-carbinol (I3C) is a phytochemical found = in=20 cruciferous vegetables, such as cabbage and cauliflower. = Epidemiologic=20 studies suggest a correlation between a diet high in such = vegetables and=20 reduced breast cancer rate (Graham=20 et al, 1982). In animal studies, a diet high in these=20 vegetables inhibited chemical carcinogen-induced tumours; and = dietary=20 supplementation with I3C could prevent oestrogen-dependent tumours = (breast, cervical, endometrial cancers) (Bradlow=20 et al, 1991; Kojima=20 et al, 1994; Jin=20 et al, 1999). In clinical studies, I3C caused = regression of=20 cervical intraepithelial neoplasia (Bell=20 et al, 2000) and regression or a decreased growth rate = of=20 recurrent laryngeal polyps (Rosen=20 et al, 1998). Indole-3-carbinol anticancer activity is=20 attributed, in part, to its anti-oestrogenic activity: it = stimulates=20 2-hydroxylation and inhibits 16-hydroxylation of oestrone, leading = to inactive=20 oestrone metabolites (Michnovicz=20 and Bradlow, 1990). Indole-3-carbinol may also interact = directly with=20 the oestrogen receptor (ER-) and inhibit its activity (Jin=20 et al, 1999); and it cooperates with Tamoxifen to = inhibit=20 breast cancer cell proliferation (Cover=20 et al, 1999).

Indole-3-carbinol also exerts = oestrogen-independent=20 actions. It can inhibit cell cycle progression, induce apoptosis, = and=20 inhibit tumour invasion and metastasis, even in ER--negative cells (Meng=20 et al, 2000a, 2001;=20 Bonnesen=20 et al, 2001; Chen=20 et al, 2001). Indole-3-carbinol downregulates = expression of a=20 G1 cyclin-dependent kinase (CDK6) and upregulates a CDK inhibitor=20 (p21^Cip1) (Cover=20 et al, 1998). The major active metabolite of I3C,=20 diindolylmethane (DIM), induces expression of GADD45, a DNA damage-responsive gene and = putative=20 tumour suppressor (Carter=20 et al, 2002). Indole-3-carbinol can activate two = pathways=20 linked to cancer prevention: (1) aryl hydrocarbon receptor (AhR)=20 signalling (which leads to expression of phase I enzymes (e.g., = CYP1A1)=20 via the xenobiotic response element) and (2) antioxidant/electrophilic response element signalling = (resulting=20 in expression of phase II detoxifying enzymes: e.g., = oxido-reductases and=20 glutathione-S-transferases) (Chen=20 et al, 1998; Hayes=20 and McMahon, 2001; Kwak=20 et al, 2002). Thus, the ability of I3C to induce = enzymes that=20 metabolise genotoxic agents may contribute to cancer=20 prevention.

The ability of = I3C and DIM=20 to inhibit growth of human prostate cancer cells has raised = interest in=20 I3C for prostate cancer prevention. Thus, DIM inhibited=20 dihydrotestosterone (DHT)-stimulated cell proliferation and = DHT-induced=20 activation of the prostate-specific antigen promoter in LNCaP = cells, by=20 acting as an AR antagonist (Le=20 et al, 2003). Indole-3-carbinol induced growth arrest = by=20 upregulation of G1 cell cycle inhibitors (p21^Cip1 and=20 p27^Kip1) in androgen-independent PC-3 prostate cancer = cells (Chinni=20 et al, 2001). Indole-3-carbinol and DIM can induce=20 p53-independent apoptosis in prostate cancer cells, in part, due = to=20 inhibition of the NF-B and c-Akt signalling pathways (Chinni=20 et al, 2001; Nacheson-Kedmi=20 et al, 2003).

We = have shown=20 that I3C upregulates expression of the breast cancer = susceptibility gene-1=20 (BRCA1) (Meng=20 et al, 2000a 2000b,=20 2001;=20 Carter=20 et al, 2002). Here, we report that: (1) both I3C and = genistein,=20 a soy isoflavone with cancer preventive activity for prostate = cancer and=20 other tumour types, upregulate both BRCA1 and BRCA2; (2) the BRCA = genes=20 contribute to some functional activities of I3C and genistein; and = (3)=20 BRCA induction may be due, in part, to stimulation of endoplasmic=20 reticulum stress signalling. These findings have implications for=20 understanding the mechanism(s) of action of these phytochemical = cancer=20 prevention agents.

3D""=20

MATERIALS AND = METHODS

Sources of=20 reagents

Indole-3-carbinol and=20 genistein were obtained from the Sigma Chemical Co. (St Louis, MO, = USA)=20 and dissolved in a small amount of dimethylsulphoxide (DMSO) prior = to=20 dilution in cell culture medium. 17-Estradiol and DHT were also = purchased from=20 Sigma. Thapsigargin and tunicamycin were obtained from Sigma, = dissolved in=20 DMSO, and stored at -20=B0C.

Cell=20 lines and culture

Human = breast=20 (MCF-7 and T47D) and prostate (DU-145, PC-3, and LNCaP) cancer = cells were=20 obtained from the American Type Culture Collection (Manassas, VA, = USA).=20 All cell lines except LNCaP were grown in Dulbecco's modified = Eagle's=20 medium (DMEM) plus 5% (MCF-7, DU-145, and PC-3) or 10% (T47D) (v=20 v^-1) fetal calf serum, L-glutamine (5=20 mM), nonessential amino acids (5 = mM),=20 penicillin (100 U ml^-1), and streptomycin (100 g ml^-1) (BioWhittaker, = Walkersville,=20 MD, USA). LNCaP cells were grown in RPMI 1640 medium plus 10% = fetal calf=20 serum and the above additives. Standard cell culture methodology = was=20 employed (Fan=20 et al, 1998, 2001a,=20 2001b).

Expression vectors and reporter=20 plasmids

Wild-type BRCA1 = (wtBRCA1)=20 cDNA, cloned into the pcDNA3 expression vector (Invitrogen), was = described=20 earlier (Fan=20 et al, 1998). To express BRCA2, a full-length human = BRCA2 cDNA=20 (provided by Dr Qingshen Gao, New England Medical Center, Boston, = MA, USA)=20 was cloned into the pCMV-Tag2B vector (Stratagene). The human = ER- expression vector and the = oestrogen-responsive=20 reporter ERE-TK-Luc were described before (Fan=20 et al, 1999b, 2001a).=20 Wild-type AR expression vector pSG5-AR and the androgen-responsive = reporter plasmid ARE-TK-Luc were provided by Dr Chawshang Chang=20 (University of Rochester, Rochester, NY, USA). The ARE-TK-Luc = reporter=20 contains an androgen-response element upstream of a minimal = thymidine=20 kinase (TK) promoter driving the luciferase = gene.

Luciferase reporters driven by the wild-type = endoplasmic=20 reticulum stress-response element (ERSEwt-Luc), a mutant ERSE=20 (ERSEmut-Luc, a negative control), and the ERSE-II element = (ERSEII3x-Luc)=20 in the pGL3 vector were generously provided by Dr Kazutoshi Mori = (HSP=20 Research Institute, Kyoto Research Park, Kyoto, Japan) (Yoshida=20 et al, 1998; Yamamoto=20 et al, 2004). A CHOP (C/EBP = homologous=20 protein) promoter-luciferase reporter in the pGL3 vector = (CHOP-Luc) was=20 provided by Dr Pierre Fafournoux (Unite de Nutrition et = Metabolisme=20 Proteique, INRA de Theix, Saint Genes Champanelle, France) (Bruhat=20 et al, 2000). A dominant negative (DN) PERK expression = vector=20 in the pcDNA3 vector (DN-PERK) was kindly provided by Dr Annette C = Dolphin=20 (University College London, London, UK) (Page=20 et al, 2004). The DN-ATF4 expression vector was = provided by Dr=20 Steve F Abcouwer (University of New Mexico School of Medicine,=20 Albuquerque, NM, USA) (Roybal=20 et al, 2004), while the DN-IRE1 expression vector was = provided=20 by Dr David Ron (Skirball Institute of Biomolecular Medicine, New = York=20 University School of Medicine, New York, NY, USA) (Wang=20 et al, 1998).

Cell=20 viability (MTT) assays

Cell=20 viability was determined following the treatments indicated in the = figure=20 legends, as described earlier (Fan=20 et al, 1998, 1999a).=20 For siRNA treatments, subconfluent proliferating cells in 96-well = dishes=20 were transfected with BRCA1 or BRCA2 siRNA (50 nM = =B4 72 h; see below), or mock-treated = (transfection=20 reagent only); exposed to different doses of I3C (or vehicle = (DMSO) only)=20 for 24 h; and then assayed for MTT dye reduction. For = overexpression=20 experiments, the cells were transfected overnight with wtBRCA1 or = wtBRCA2=20 expression vectors (0.06 g plasmid DNA per well), washed, and = postincubated for another 24 h to allow gene expression, prior to = exposure=20 to I3C. Cell viability was expressed relative to control cells = treated=20 with DMSO only (0 I3C) as mean=B1s.e.m. = of 10=20 replicate wells.

Knockdown = of BRCA1=20 or BRCA2 using small interfering RNAs = (siRNAs)

The BRCA1-siRNA and control (scrambled sequence) = siRNAs=20 were described earlier (Xiong=20 et al, 2003). All siRNAs were chemically synthesised by = Dharmacon, Inc. For siRNA treatments, subconfluent proliferating = cells=20 were transfected with 50 nM of siRNA using the = siPORT Amine=20 transfection reagent (Ambion). For both BRCA1 and BRCA2, maximal = reduction=20 of protein levels required a 72-h incubation with the siRNA. Prior = studies=20 have established that under these conditions, none of the siRNAs = caused=20 cytotoxicity, based on cell morphology and MTT assays. The = sequences used=20 to synthesise the siRNAs are listed below:

BRCA1-siRNA	5'-AATGCCAAAGTAGCTAATGTA-3'
Control-siRNA=20	5'-CGATAGATACACAGATTGAAT-3'
BRCA2-siRNA	5'-AACTGAGCAAGCCTCAGTCAA-3'

Oestrogen receptor- 3Dalpha=20

transcriptional activity=20 assay

Oestrogen = receptor- activity was measured via transient = transfection assays, using an oestrogen-responsive luciferase = reporter (Fan=20 et al, 1999b, 2001a).=20 Briefly, subconfluent proliferating cells in 24-well dishes were=20 cotransfected overnight with a wild-type ER- expression vector (pSG5-ER-) and the ERE-TK-Luc reporter (0.25 = g of each plasmid per well), in the = presence of=20 Lipofectamine=D4 (Life Technologies, = Carlsbad, CA,=20 USA). The cells were washed to remove the excess plasmid and=20 Lipofectamine; allowed to recover for several hours; and = postincubated for=20 24 h in phenol red-free medium containing 2% charcoal-stripped = fetal calf=20 serum, with the indicated agents (17--estradiol (E2, 1 M) and/or I3C and/or = genistein). The=20 doses of each agent are indicated in the figures. Luciferase = activity was=20 determined; and the values were expressed relative to the positive = control=20 (+E2, no I3C or genistein), as means=B1s.e.m.'s of=20 three independent experiments, with each assay condition tested in = four=20 replicate wells per experiment. To monitor transfection = efficiency, cells=20 were cotransfected with control plasmid pRSV--gal to allow measurement of -galactosidase = activity.

Androgen receptor (AR) transcriptional = activity=20 assays

Androgen receptor = activity=20 was measured via transient transfection assays, using an=20 androgen-responsive reporter (ARE-TK-Luc). Assays were performed = as=20 described above, except that AR-negative PC-3 cells were = cotransfected=20 with a wild-type human AR expression vector (pSG5-AR); and the = cells were=20 stimulated with DHT (10 nM) for 24 h, again in the = absence=20 or presence of the specified doses I3C or genistein. The = expression of=20 luciferase activity and the number of replicate assays were the = same as=20 described above. Each experiment was repeated at least twice to = assure=20 reproducibility.

mRNA=20 assays

mRNA expression = was=20 determined by rigorously controlled semiquantitative RT-PCR assays. For each amplified product, the = PCR=20 reaction conditions and cycle numbers were individually adjusted = so that=20 all reactions occurred within the linear range of product = amplification.=20 The detailed methods for RNA isolation, cDNA synthesis, and = RT-PCR analyses for BRCA1, BRCA2, and -actin (control gene) have been = described before=20 (Fan=20 et al, 1998, 1999a;=20 Xiong=20 et al, 2003). For AR, the PCR primers were as follows:=20 5'-TGTTTTCCCCCTCTTCCTT-3' (forward) and = 5'-TCCTTTTTTCCAGCATAGACC-3'=20 (reverse). The PCR products were analysed by electrophoresis = through 0.8%=20 agarose gels containing 0.1 mg ml^-1 of ethidium = bromide, and=20 the gels were photographed under ultraviolet light. The mRNA = levels were=20 quantitated by densitometry of the cDNA bands and expressed = relative to=20 -actin. At least two independent = experiments=20 were performed for each cell type studied.

Protein assays

Cell lysates were prepared and Western blotting = was=20 performed as described earlier (Fan=20 et al, 1998, 1999a).=20 Equal aliquots of total cell protein (50 g per lane) were electrophoresed on = SDS-polyacrylamide gradient gels, transferred to = nitrocellulose membranes (Millipore, Billerica, MA, USA), and = blotted=20 using these primary antibodies: BRCA1 (C-20, rabbit polyclonal, = Santa Cruz=20 Biotechnology, 1 : 200); BRCA2 (C-19, Santa Cruz, 1 : 200); and = actin=20 (I-19, goat polyclonal, Santa Cruz, 1 : 500). The proteins bands = were=20 visualised using the enhanced chemiluminescence system (Amersham), = with=20 coloured markers (BioRad) as molecular size standards. Protein = bands were=20 quantitated by densitometry, and the values were expressed = relative to=20 actin (control for loading and transfer). At least two independent = experiments were performed for each cell type = studied.

Statistical = comparisons

Where appropriate, statistical comparisons of the = experimental results were made using the two-tailed Student's=20 t-test.

3D""=20

RESULTS

Indole-3-carbinol upregulates BRCA1 and BRCA2 = expression=20 in breast and prostate cancer cells

We previously showed that I3C stimulates BRCA1 = expression=20 in human cervical and breast cancer cells (Meng=20 et al, 2000a, 2000b,=20 2001;=20 Carter=20 et al, 2002). Here, we tested the effect of I3C on = BRCA1 and=20 BRCA2 expression in breast and prostate cancer cells. Using = rigorously=20 controlled semiquantitative RT-PCR and=20 densitometry analysis, we found that a dose of I3C (60 M) that causes little = or no=20 cytotoxicity caused a time-dependent increase in BRCA1 and BRCA2 = mRNA=20 levels in two breast cancer cell lines, MCF-7 and T47D (Figure=20 1A and B). BRCA1 levels were increased at the earliest time = point=20 tested (1 h), reached near maximum by 6-8 h, and=20 were still elevated at 48 h. For T47D, BRCA2 mRNA levels were also = elevated by 1-2 h and remained elevated = throughout the experiment. MCF-7 cells also showed strong = time-dependent=20 induction of BRCA2 by I3C, but consistent increases in BRCA2 mRNA = levels=20 were only observed at 6 h and later. Indole-3-carbonil caused=20 dose-dependent induction of BRCA1 and BRCA2 mRNA (measured at 24 = h)=20 starting at 20-40 M (Figure=20 1C and D). Little or no changes in expression of the control = gene=20 (-actin) were evident in any of these = experiments.

Figure 1
Indole-3-carbinol (I3C) upregulates BRCA1 and = BRCA2=20 mRNA expression in human breast cancer cells in a time- and=20 dose-dependent manner. For time course studies, subconfluent = proliferating MCF-7 (A) or T47D (B) cells were = treated=20 with I3C (60 M) for = different times and=20 harvested for mRNA analysis by semiquantitative RT-PCR. For dose-response=20 studies, MCF-7 (C) or T47D (D) cells were = treated with=20 different doses of I3C for 24 h and harvested for mRNA = analysis. The=20 PCR bands were quantified by densitometry and expressed = relative to=20 the control gene, -actin. The densitometry = values are=20 means=B1s.e.m.'s of at least two = independent=20 experiments.

We tested the effect of I3C on BRCA protein = levels by=20 Western blotting with quantitation of the protein bands by = densitometry.=20 BRCA protein levels were upregulated by I3C in a time- and = dose-dependent=20 fashion in breast (MCF-7 and T47D) and prostate (LNCaP and DU-145) = cancer=20 cells (Figure=20 2). For the breast cancer cells, increased BRCA2 protein = levels were=20 first observed after 4-8 h of I3C (60 = M); while increases = in BRCA1=20 levels were detected earlier, but were relatively small in = magnitude at=20 early time points (Figure=20 2A and B). The dose-response = studies of MCF-7=20 and T47D cells revealed significant induction (>2-fold) of = BRCA1 and=20 BRCA2 protein levels at the lowest dose of I3C tested, 20 M (Figure=20 2C and D). In Figure=20 2C, the BRCA2 protein induction is not the same as that of the = mRNA=20 (Figure=20 1C). This may be due to inaccuracies in the densitometry = quantitation=20 of the RT-PCR (especially when bands = are weak),=20 the fact that the protein and mRNA experiments were performed at = different=20 times, or the fact that I3C might have an additional effect on = protein=20 stability, which we cannot rule out.

Figure 2
Indole-3-carbinol upregulates BRCA1 and BRCA2 = protein=20 levels in human breast and prostate cancer cells in a time- = and=20 dose-dependent manner. For time course studies, subconfluent = proliferating MCF-7 (A), T47D (B), DU-145 = (E),=20 and LNCaP (F) cells were treated with I3C (60 M) for various = times and=20 harvested for Western blot analysis to detect the BRCA1, = BRCA2, or=20 actin (control for loading and transfer) proteins. For = dose-response studies, MCF-7 (C), = T47D=20 (D), DU-145 (G), or LNCaP (H) cells = were=20 treated with the indicated dose of I3C for 24 h and then = assayed for=20 BRCA1 and BRCA2 protein expression. The protein bands were=20 quantitated by densitometry and expressed relative to actin. = The=20 densitometry values are means=B1s.e.m.'s of=20 at least two independent=20 experiments.

Time course studies of prostate cancer cell lines = showed a=20 delay in the induction of BRCA2 by I3C (first observed at 6 h) = relative to=20 that of BRCA1 (1 h) (Figure=20 2E and F). As for breast cancer cells, BRCA1 and BRCA2 levels = were=20 increased by 2-fold at the lowest dose of I3C (20 M) (Figure=20 2G and H). Although there was some variability from cell line = to cell=20 line, these studies show reproducible induction of BRCA1 and BRCA2 = by I3C,=20 with increases in BRCA1 and BRCA2 protein levels at an I3C dose of = 60=20 M at 24 h of (5-10)-fold for the breast cancer cell lines = and (8-16)-fold for the prostate cancer cell lines. = Note: In=20 the studies shown in Figures=20 1 and 2,=20 the densitometry values are the means of at least two independent=20 experiments.

Genistein = upregulates=20 BRCA1 and BRCA2 expression

Genistein is a soy isoflavone that functions, in = part, as a=20 phytoestrogen and a phytoandrogen (Wang=20 et al, 1996; Maggiolini=20 et al, 2002). Since genistein is proposed as a = chemoprevention=20 agent for several tumour types (Mentor-Marcel=20 et al, 2001; Lamartiniere=20 et al, 2002), including breast and prostate cancers, we = tested=20 its ability to induce BRCA expression. Genistein caused dose- and=20 time-dependent increases in BRCA1 and BRCA2 protein levels in two=20 oestrogen-responsive breast cancer cell lines (MCF-7 and T47D) (Figure=20 3D). Induction of BRCA1 occurred after 1 h of genistein = exposure (5=20 M); while the = induction of BRCA2=20 was delayed until 6-8 h (Figure=20 3A and B). For both cell lines, increases in BRCA1 levels of=20 >2-fold were observed at the lowest dose of genistein tested = (0.5=20 M); while similarly = robust=20 increases in BRCA2 levels required higher genistein doses (1-2.5 M) (Figure=20 3C and D).

Figure 3
Genistein=20 upregulates BRCA1 and BRCA2 protein levels in breast cancer = cells.=20 For time course studies, subconfluent proliferating MCF-7=20 (A), T47D (B), DU-145 (E), and LNCaP = (F)=20 cells were treated with genistein (5 M) for the = indicated times=20 and harvested for Western blotting to detect the BRCA1, = BRCA2, or=20 actin proteins. For dose-response = studies,=20 MCF-7 (C), T47D (D), DU-145 (G), or = LNCaP=20 (H) cells were treated with the indicated dose of = genistein=20 for 24 h and assayed for BRCA1 and BRCA2 protein expression, = as=20 described above. The densitometry values represent = means=B1s.e.m.'s of at least two independent = experiments.

Genistein also caused time- and dose-dependent = increases in=20 BRCA levels in androgen-sensitive (LNCaP) and insensitive (DU-145) = prostate cancer cells. For these cell lines, increases in BRCA1 = levels of=20 2-fold occurred at 1 h; while similar increases in = BRCA2=20 levels occurred at 4-8 h (Figure=20 3E and F). When measured at 24 h, significant increases in = BRCA1=20 levels required doses of 0.5-1.0 = M; while increases in = BRCA2=20 levels required 2.5 M of genistein (Figure=20 3G and H). Increases in BRCA levels after exposure to 5 = M of genistein for 24 = h ranged=20 (4-12)-fold for breast cancer cells and = (5-17)-fold for prostate cancer cells. The = densitometry=20 values in Figure=20 3 are the means of at least two independent=20 experiments.

Role of BRCA1 = in the=20 induction of BRCA2 by I3C and by genistein

Several factors suggest that the phytochemical = induction of=20 BRCA2 is due, in part, to BRCA1. Thus, BRCA1 and BRCA2 are = coordinately=20 regulated during development and during cell cycle progression (Rajan=20 et al, 1996, 1997);=20 and exogenous BRCA1 upregulates expression of BRCA2 in cultured = cells (Fan=20 et al, 1998). BRCA1 and BRCA2 are also coregulated in = response=20 to DNA-damaging agents and other cytotoxins (Andres=20 et al, 1998; Fan=20 et al, 1999a). To determine the role of BRCA1 in the = induction=20 of BRCA2, we utilised specific BRCA1 and BRCA2 siRNAs. The = BRCA1-siRNA was=20 validated in a prior study (Xiong=20 et al, 2003). As illustrated in Figure=20 4A, a single application of 50 nM of = BRCA1-siRNA caused=20 a loss of BRCA1 and BRCA2 proteins by 48-72 h,=20 while a control-siRNA had no effect on BRCA1 or BRCA2=20 levels.

Figure 4
Dependence of=20 phytochemical-induced expression of BRCA2 on BRCA1. = (A)=20 BRCA1-siRNA causes time-dependent loss of BRCA1 and BRCA2 in = MCF-7=20 cells. Subconfluent proliferating cells were treated with=20 BRCA1-siRNA (left) or control-siRNA (right) (50 = nM)=20 for different times, harvested, and Western blotted for = BRCA1,=20 BRCA2, and actin. (B) Effect of BRCA1-siRNA on BRCA2 = protein=20 levels and vice versa in DU-145 cells. Cells were = treated=20 with BRCA1, BRCA2, or control-siRNA (50 nM) = for 72 h=20 and Western blotted for BRCA1, BRCA2, and actin. Results are = shown=20 for two separate cell treatments and protein isolations on = the same=20 blot. (C) Effect of wtBRCA1 on BRCA2 protein levels = and=20 vice versa in DU-145 cells. Cells were transfected = overnight=20 with wtBRCA1, wtBRCA2, or empty pcDNA3 vector, washed, = postincubated=20 for 24 h to allow gene expression, harvested, and Western = blotted=20 for BRCA1, BRCA2, and actin. Results are shown for two = separate cell=20 treatments and protein isolations on the same blot. The = densitometry=20 values are means=B1ranges of two = experiments.=20 (D) Effect of BRCA1 and BRCA2 siRNAs on BRCA = induction by=20 I3C. DU-145 cells were preincubated with the indicated siRNA = (50=20 nM =B4 72 h) or no = siRNA=20 (transfection reagent only), then treated with I3C (40 = M) for 24 h, = and then=20 harvested for Western blotting. (E) Effect of BRCA1 = and BRCA2=20 siRNA on induction of BRCA1 and BRCA2 by genistein. DU-145 = cells=20 were preincubated with the indicated siRNA (50 = nM=20 =B4 72 h), treated with genistein = (5 M) for 24 h, = and harvested=20 for Western blotting as above. (F) Induction of BRCA1 = and=20 BRCA2 by a combination of I3C plus genistein. MCF-7 or = DU-145 cells=20 were treated with low doses of I3C (25 M) and/or genistein (1 M) for 24 h and = harvested=20 for Western blotting. The densitometry values are means=B1ranges of two independent = experiments.=20 (G) Effect of ICI182,780 on phytochemical induction = of BRCA1=20 in MCF-7 cells. Proliferating cells were incubated with the=20 indicated agents for 24 h and then harvested for Western = blotting=20 for BRCA1, ER-, or actin. (H) Effect = of BRCA1=20 knockdown and phytochemicals on ER- protein levels. MCF-7 cells = were=20 pretreated with BRCA1 or control siRNA as described above, = exposed=20 to the indicated doses of I3C or genistein for 24 h, and = then=20 Western blotted for ER-, BRCA1, or=20 actin.

Consistent with these findings, BRCA1-siRNA = caused loss of=20 BRCA1 and BRCA2 proteins in DU-145 cells, but the converse was not = true=20 (Figure=20 4B). Thus, BRCA2-siRNA caused loss of BRCA2 protein, but BRCA1 = was=20 unaffected or only slightly decreased (Figure=20 4B). The control-siRNA had little or no effect on BRCA1 or = BRCA2. In=20 overexpression studies, a wild-type (wt) BRCA1 expression vector = caused=20 significant induction of BRCA2 levels; whereas wtBRCA2 caused a = more=20 modest rise in BRCA2 levels (Figure=20 4C). Next, we tested the role of BRCA1 in the induction of = BRCA2=20 levels by I3C and by gensitein. In DU-145 cells pretreated with=20 BRCA1-siRNA, there was little or no detectable BRCA2 in control,=20 I3C-treated, or genistein-treated cells (Figure=20 4D and E, respectively). In cells treated with BRCA2-siRNA, = BRCA2 was=20 nearly undetectable in control and phytochemical-treated cells. = However,=20 BRCA1 was significantly induced by both I3C and genistein. A = control-siRNA=20 had no effect on the expression or induction of BRCA proteins. = These=20 findings suggest that the induction of BRCA2 by phytochemicals is=20 dependent, in part, upon BRCA1, but not vice=20 versa.

Combination of = I3C plus=20 genistein

We tested the = effects of=20 a combination of low doses of I3C (25 M) and genistein (1 = M) on BRCA protein = levels in=20 MCF-7 and DU-145 cells. The combination of (I3C+genistein) had a = greater=20 effect on BRCA induction than either agent alone (Figure=20 4G). These effects appeared to be supra-additive or = synergistic for=20 BRCA1 in MCF-7 cells and for BRCA2 in both cell types, although we = did not=20 perform studies using a range of different doses. Thus, 1 M of genistein by = itself caused=20 only a modest increase in BRCA2 levels; but the combination of=20 (I3C+genistein) caused a much larger increase in BRCA2 levels than = did I3C=20 alone.

Effect of = inhibition of=20 ER- 3Dalpha=20

on BRCA1 = expression

To determine if ER- might have a role in the induction = of BRCA1 by=20 phytochemicals, MCF-7 cells were treated with I3C or genisetin in = the=20 absence or presence of ICI182,780 (Fulvestrant), an anti-oestrogen = that=20 causes degradation of ER-. Here, ICI182,780 caused loss of = ER- protein but had no effect on the = ability of I3C=20 or genistein to induce BRCA1 protein (Figure=20 4G). As illustrated in Figure=20 4H, neither BRCA1-siRNA, nor I3C, nor genistein had ER- protein levels in MCF-7 cells. = Taken together=20 with the findings that I3C and genistein can induce BRCA = expression in=20 ER--negative cell types (e.g., DU-145), = these=20 results suggest that the induction of BRCA expression by = phytochemicals is=20 not mediated through the oestrogen receptor.

Role of BRCA1 in mediating some biological = actions of=20 I3C and genistein

While = it is clear=20 that I3C and genistein induce BRCA gene expression in human cancer = cells,=20 the roles of the BRCA genes in mediating the biologic responses to = these=20 phytochemicals is not established. We tested these roles utilising = the=20 BRCA1 and BRCA2 siRNA and other reagents.

Cytotoxicity: At high doses (100 M), I3C causes = cytotoxicity and=20 apoptosis in cancer cell lines (Chen=20 et al, 2001; Chinni=20 et al, 2001; Rahman=20 et al, 2003; Sarkar=20 et al, 2003). Exogenous BRCA1 causes increased = susceptibility=20 to apoptosis due to DNA-damaging agents (e.g., adriamycin), = although=20 wtBRCA1 does not induce apoptosis by itself (Fan=20 et al, 1998, 2001b).=20 We tested the effect of manipulating BRCA levels on I3C = cytotoxicity using=20 MTT assays. Figure=20 5A shows the ability of BRCA1-siRNA and BRCA2-siRNA to reduce = BRCA1=20 and BRCA2 protein levels, respectively, by 48-72=20 h. In three different cell lines (MCF-7, T47D, and DU-145), we = found that=20 BRCA1-siRNA protected cells against I3C cytotoxicity (Figure=20 5C, E and G). BRCA1-siRNA-treated cells usually showed = survival rates=20 about 15=B15% higher than = control-siRNA-treated=20 cells (P<0.001, two-tailed t-tests), although the = degree=20 of protection by BRCA1-siRNA was greater for DU-145 cells at = 300-400 M of I3C (21-32%).

Figure 5
Contribution=20 of BRCA1 and BRCA2 to I3C-mediated cytotoxicity. (A) = The=20 effects of BRCA1-siRNA (48 and 72 h) and BRCA2-siRNA (72 h) = (50=20 nM) on BRCA1 and BRCA2 protein levels, = respectively,=20 in MCF-7 cells. MCF-7 (B and C), T47D = (D and=20 E), and DU-145 (F and G) cells were=20 experimentally manipulated to increase (wtBRCA1) or decrease = (BRCA1-siRNA) BRCA1 levels, treated with different doses of = I3C, and=20 tested for cell viability using MTT assays. In (H) = and=20 (I), DU-145 cells were manipulated to increase = (wtBRCA2) or=20 decrease (BRCA2-siRNA) BRCA2 levels, exposed to different = doses of=20 I3C, and tested for cell viability using MTT assays.=20 Methodology (B-I). To=20 increase BRCA1 levels, subconfluent cells in 96-well dishes = were=20 transfected with wtBRCA1 overnight (see Materials and = Methods),=20 washed, postincubated for 24 h, exposed to different doses = of I3C=20 for 24 h, and assayed for MTT dye reduction. To decrease = BRCA1=20 levels, cells were pretreated with BRCA1- or control-siRNA = (50=20 nM =B4 72 h) or=20 mock-transfected (control) and assayed for sensitivity to = I3C as=20 above. For BRCA2 experiments, DU-145 cells were transfected = with=20 wtBRCA2 or treated with BRCA2- or control-siRNA (as above) = and=20 assayed as described above for sensitivity to I3C. Cell = viability=20 values are expressed relative to the 0 I3C control and are=20 means=B1s.e.m.'s for 10 replicate = wells.=20 Statistical comparisons. Cell viability comparisons = were made=20 using two-tailed t-tests. Significant differences = were as=20 follows: MCF-7 wtBRCA1 vs control, P<0.001 = at=20 100-400 M I3C; MCF-7 = BRCA1-siRNA=20 vs control, P<0.001 at 200-500 M I3C; T47D = wtBRCA1=20 vs control, P<0.001 at 100-500 M I3C; T47D = BRCA1-siRNA=20 vs control, P<0.001 at 200-500 M I3C; DU-145 = wtBRCA1=20 vs control, P<0.001 at 100-400 M I3C; DU-145 = BRCA1-siRNA=20 vs control, P<0.001 at 100-500 M I3C; DU-145 = wtBRCA1=20 vs control, P<0.001, 100-400 M I3C; and = DU-145=20 BRCA2-siRNA vs control, P<0.001 at 200-500 M=20 I3C.

In=20 contrast, cells transfected with a wtBRCA1 gene were more = sensitive to I3C=20 than control cells (P<0.001) (Figure=20 5B, D, and F). At 200-400 M of I3C, MCF-7 and = T47D cells=20 transfected with wtBRCA1 showed survival rates about 15-20% lower than control-transfected cells; = while=20 wtBRCA1-transfected DU-145 cells showed 15-40%=20 lower survival than control-transfected cells at 100-400 M I3C. These findings = suggest=20 that BRCA1 modulates the cytotoxicity of I3C and that endogenous = BRCA1=20 contributes the cytotoxicity of I3C.

Since the BRCA1-siRNA downregulates BRCA2 levels, = we tested=20 the ability of BRCA2 to modulate sensitivity to high doses of I3C. = As was=20 true for BRCA1, a wtBRCA2 expression vector sensitised DU-145 = cells to I3C=20 (Figure=20 5H); while BRCA2-siRNA conferred decreased sensitivity to I3C=20 (P<0.001 at all doses) (Figure=20 5I). Taken together with the previous results, these findings = suggest=20 that (1) both BRCA genes modulate cellular sensitivity to I3C and = (2) the=20 modulation of sensitivity to I3C by BRCA1 is due, in part, to = alterations=20 in BRCA2 levels.

Oestrogen = receptor-- 3Dalpha=20

signalling: We showed that I3C = causes=20 dose-dependent inhibition of estradiol (E2)-stimulated ER- activity in cervical and breast = cancer cells,=20 by the use of an E2-responsive reporter (ERE-TK-Luc) and by = testing the=20 effect of I3C on expression of endogenous E2-responsive genes (Meng=20 et al, 2000b). Since wtBRCA1 strongly inhibits = ER- signalling (Fan=20 et al, 1999b), we hypothesised that BRCA1 might = contribute to=20 the inhibition of ER- activity by I3C. Thus, we assayed = the effects=20 of BRCA siRNAs on the ability of I3C and genistein to inhibit=20 E2-stimulated ER- activity (Figure=20 6). While genistein is called a 'phytoestrogen' because it has = weak=20 oestrogenic activity in the absence of E2, it acts as an inhibitor = of=20 ER- in the presence of E2. Thus, = genistein caused=20 dose-dependent inhibition of E2-stimulated ER- activity in MCF-7 cells (data not = shown). In=20 this study, we did not observe pro-oestrogenic effects of = genistein.=20 However, we did not specifically test conditions that would elicit = such=20 effects.

Figure 6
Contribution=20 of BRCA genes to regulation of ER- and AR activity by I3C and = genistein.=20 (A) Rescue of I3C inhibition of E2-stimulated = ER- activity by BRCA1-siRNA. = MCF-7 cells were=20 pretreated with BRCA1-siRNA, BRCA2-siRNA, control-siRNA (50=20 nM =B4 72 h), or = no siRNA=20 (vehicle only). After the first 48 h of siRNA treatment, = they were=20 transfected with the ERE-TK-Luc reporter overnight, washed,=20 postincubated=B117-estradiol (E2, 1 M) and =B1I3C (100 M) for 24 h, = and tested for=20 luciferase activity. Values are expressed relative to the = +E2=20 positive control (no siRNA, no I3C) and are means=B1s.e.m.'s of three independent = experiments. In=20 each experiment, each assay condition was tested in four = replicate=20 wells, and the values were averaged. BRCA1 (but not BRCA2 or = control) siRNA reversed the inhibition of E2-stimulated = ER- activity by I3C = (P<0.001).=20 (B) Rescue of genistein inhibition of E2-stimulated=20 ER- activity by BRCA1-siRNA. The = experiment=20 was performed as described above, except that the cells were = treated=20 =B1genistein (5 M) instead of = I3C.=20 Luciferase values are expressed relative to the +E2 positive = control=20 (no siRNA, no genistein) and are means=B1s.e.m.'s of three independent = experiments, with=20 each assay condition tested in four replicate wells per = experiment.=20 BRCA1 (but not BRCA2 or control) siRNA reversed the = inhibition of=20 E2-stimulated ER- activity by genistein=20 (P<0.001). (C, D) Contribution of = BRCA1 to=20 inhibition of DHT-stimulated AR activity by I3C and = genistein. LNCaP=20 (C) or PC-3 (D) cells were pretreated with=20 BRCA1-siRNA, control-siRNA (50 nM =B4 72 h), or no siRNA. LNCaP cells, = which are=20 AR-positive, were transfected with an androgen-responsive = reporter=20 (ARE-TK-Luc); while PC-3 cells, which are AR-negative, were=20 cotransfected with an AR expression vector plus ARE-TK-Luc. = The=20 cells were treated with dihydrotestosterone (DHT, 10=20 nM), I3C (25 M), and/or genistein (1.0 M) for 24 h and = assayed for=20 luciferase activity. BRCA1-siRNA enhanced DHT-stimulated AR = activity=20 and partially rescued the inhibition of AR activity by I3C = and=20 genistein (left panels). The asterisks indicate a = significant=20 comparison (P<0.01). (E) Effect of = BRCA1-siRNA and=20 phytochemicals on AR protein levels in LNCaP cells. Cells = were=20 pretreated with BRCA1 or control siRNA and then treated with = I3C,=20 genistein, or DHT as described in (C). The cells were = then=20 harvested and Western blotted for AR or actin. (F) = Effect of=20 BRCA1-siRNA on AR mRNA levels. LNCaP cells were pretreated = with=20 BRCA1- or control-siRNA, treated with DHT for 24 h, and = harvested=20 for semiquantitative RT-PCR to = detect=20 BRCA1, AR, or -actin.

Figure=20 6A shows the effect of pretreatment with BRCA siRNAs on = inhibition of=20 E2-stimulated ER- activity by I3C. These data are the = means=B1s.e.m.'s of three independent experiments. = BRCA1 (but=20 not BRCA2) siRNA caused a modest increase in E2-stimulated = ER- activity. Under conditions in which = I3C caused=20 >90% inhibition of ER- activity, pretreatment with = BRCA1-siRNA (but=20 not BRCA2- or control-siRNA) substantially restored E2-stimulated=20 ER- activity (P<0.001, = two-tailed=20 t-test). Similar results were obtained using genistein (Figure=20 6B). Thus, BRCA1 (but not BRCA2 or control) siRNA = significantly=20 reversed the genistein-mediated inhibition of E2-stimulated = ER- activity (P<0.001). = Previously, we=20 identified an N-terminal fragment of the BRCA1 protein (amino = acids 1-302) that functioned as a DN inhibitor of = the=20 full-length wild-type BRCA1 and 'rescued' the wtBRCA1-mediated = inhibition=20 of ER- activity (Fan=20 et al, 2001a, 2001b).=20 Here, we found that transient transfection of a BRCA1 amino acid = 1-302 expression vector (DN-BRCA1) partially = rescued the=20 inhibition of E2-stimulated ER- activity by I3C alone, genistein = alone, or the=20 combination of I3C plus genistein (P<0.001) (data not = shown).=20 These findings suggest that the inhibition of E2-stimulated = ER- activity by I3C and genistein is = due, in part,=20 to BRCA1.

AR = signalling: Both=20 I3C and genistein can interact with and modulate the AR. Thus, I3C = is an=20 AR antagonist (Le=20 et al, 2003), while genistein can activate the AR in = the=20 absence of ligand but inhibit DHT-induced AR activity (Maggiolini=20 et al, 2002). We tested the role of BRCA1 in mediating = the=20 effects of low doses of I3C (25 M) or genistein (1 = M) on AR signalling. = We studied=20 LNCaP cells (an androgen-responsive cell line) using their = endogenous AR=20 and PC-3 (an androgen-insensitive cell line) using transiently = expressed=20 wild-type AR. Consistent with published findings, genistein (but = not I3C)=20 caused a modest activation of an androgen-responsive reporter = (ARE-TK-Luc)=20 in the absence of DHT (Figure=20 6C and D, right panels), while both I3C and genistein caused=20 inhibition of DHT-stimulated AR activity (P<0.001) (Figure=20 6C and D, left panels). Interestingly, pretreatment = with=20 BRCA1-siRNA caused an increase in DHT-stimulated AR activity = (relative to=20 control-siRNA or vehicle-treated cells) in the absence of I3C or = genistein=20 and partially rescued the inhibition of AR activity by I3C and = genistein=20 (P<0.01). Similar results were observed in LNCaP and = PC-3 cells.=20 Pretreatment with BRCA1-siRNA caused an increase in AR protein = levels in=20 cells treated with DHT, whereas BRCA1-siRNA by itself and = control-siRNA in=20 the absence or presence of DHT had little or no effect on AR = levels (Figure=20 6E). In contrast, BRCA1-siRNA had no effect on AR mRNA levels = in the=20 presence of DHT (Figure=20 6F). The implications of these findings are considered in the=20 Discussion.

Role of = endoplasmic=20 reticulum stress in induction of BRCA = expression

Agents that cause endoplasmic reticulum stress = induce=20 BRCA expression: A recent study showed that DIM, a major = metabolite of=20 I3C, causes an endoplasmic reticulum-like stress response, similar = to the=20 unfolded protein response in yeast (Sun=20 et al, 2004). Diindolylmethane caused phosphorylation = of=20 eucaryotic translation initiation factor 2 (EIF2A) linked to increased levels = of ATF4=20 protein; activation of IRE1 (the homologue of inositol-requiring = 1); a=20 rapid increase in the stress-specific spliced form of XBP-1 mRNA; = and=20 induction of multiple stress-response genes, including CHOP (or = GADD153),=20 GADD34, GADD45A, XBP-1, GRP78, and GRP94 (Carter=20 et al, 2002; Sun=20 et al, 2004). Here, we tested the ability of two agents = known=20 to cause an endoplasmic reticulum stress response to induce BRCA=20 expression. Incubation of T47D or MCF-7 cells with thapsigargin, a = selective inhibitor of the endoplasmic reticulum = Ca⁺²-dependent=20 ATPase, caused dose- and time-dependent induction of BRCA1 and = BRCA2 mRNA=20 expression (Figure=20 7A-C). Induction of both BRCA genes = occurred=20 after a 24-h incubation with doses as low as 50-100 nM of thapsigargin (Figure=20 7A and B), while a time course study showed that BRCA1 mRNA = was=20 induced by thapsigargin (300 nM) after 4-6 h, with BRCA2 mRNA induction occurring = slightly=20 later (Figure=20 7C). MTT assays revealed no toxicity at thapsigargin doses = 300 nM (data not shown). Western = blotting=20 revealed induction of BRCA1 protein in T47D and MCF-7 cells at = 50-100 nM of thapsigargin (Figure=20 7D and E).

Figure 7
Thapsigargin=20 and tunicamycin upregulate BRCA gene expression. (A,=20 B) Dose-response for = induction of=20 BRCA mRNAs by thapsigargin in T47D (A) and MCF-7 = (B)=20 cells. Subconfluent proliferating cells were incubated with = the=20 indicated doses of thapsigargin for 24-h and then harvested = for=20 semiquantitative RT-PCR analysis = of BRCA1,=20 BRCA2, and -actin (control gene). = (C) Time=20 course for induction of BRCA1 mRNAs by thapsigargin in MCF-7 = cells.=20 MCF-7 cells were incubated with thapsigargin (300 = nM)=20 for different time intervals up to 48-h and then harvested = for=20 semiquantitative RT-PCR analysis = of BRCA1,=20 BRCA2, and -actin. (D, E) = Dose-response for induction of BRCA1 = protein by=20 thapsigargin in T47D (D) and MCF-7 (E) cells. = Cells=20 were incubated with the indicated doses of thapsigargin for = 24-h and=20 then harvested for Western blotting to detect BRCA1 and = actin=20 (control for loading and transfer). (F, G) = Dose-response for induction of BRCA = proteins by=20 tunicamycin in T47D (F) and MCF-7 (G) cells. = Cells=20 were incubated with the indicated doses of thapsigargin for = 24-h and=20 then harvested for Western blotting to detect BRCA1, BRCA2, = and=20 actin.

We=20 also saw dose-dependent induction of BRCA1 and BRCA2 proteins by=20 tunicamycin (Figure=20 7F and G), an agent that causes an endoplasmic reticulum = stress=20 response by inhibition of protein glycosylation. These findings = suggest=20 that activation of an endoplasmic reticulum stress response by two = distinct agents upregulates the expression of BRCA1 and=20 BRCA2.

The ER = stress-response kinase=20 PERK is required for BRCA1 induction by I3C: We tested the = role of=20 several endoplasmic reticulum stress signalling proteins in I3C = induction=20 of BRCA1 and BRCA2, using DN expression vectors. PERK (EIF2AK3) is = a=20 kinase that phosphorylates EIF2A in response to endoplasmic = reticulum=20 stress, causing inhibition of protein synthesis associated with = the=20 accumulation of ATF4 protein (Rutkowski=20 and Kaufman, 2003). Transfection of a DN-PERK blocked the = ability of=20 I3C (100 M) to induce both = BRCA1 and BRCA2=20 protein levels (Figure=20 8A). However, a DN-ATF4 vector failed to inhibit I3C-induced = BRCA1 and=20 BRCA2 expression (Figure=20 8B). Finally, we tested the role of IRE1 (the homolog of yeast = inositol-requiring 1) - an endoplasmic = reticulum=20 membrane-localised kinase and endoribonuclease that is activated = in=20 response to stress (Shen=20 et al, 2001) - in mediating = BRCA=20 induction. Here, a DN-IRE1 vector failed to inhibit I3C-induced = BRCA1 or=20 BRCA2 expression (Figure=20 8C). These findings suggest that PERK, an upstream component = of=20 endoplasmic reticulum and nutritional stress-response pathways, is = required for BRCA induction.

Figure 8
Induction of=20 BRCA expression by I3C requires the kinase PERK (EIFAK3). = (A)=20 Dominant negative (DN) PERK blocks I3C induction of BRCA = protein.=20 Subconfluent proliferating MCF-7 cells were transfected = overnight=20 with control (vehicle only), empty pcDNA3 vector, or DN-PERK = (15-g plasmid DNA per 100-mm dish) = using=20 Lipofectamine=D4. The transfected = cells were=20 washed, allowed to recover for several hours, treated=B1I3C for 24-h, and harvested for = Western blotting=20 to detect BRCA1, BRCA2, or actin (control for loading and = transfer).=20 (B) Dominant negative IRE1 fails to block I3C = induction of=20 BRCA protein. Assays were performed as described in = (A),=20 except using DN-IRE1 instead of DN-PERK. (C) Dominant = negative ATF4 fails to block I3C induction of BRCA protein. = Assays=20 were performed as described in (A), except using = DN-ATF4=20 instead of = DN-PERK.

I3C, genistein, and BRCA1 stimulate = endoplasmic=20 reticulum stress signalling: Endoplasmic reticulum stress = signalling=20 is mediated, in part, by transcription via cis-acting DNA = elements=20 in target genes, including the endoplasmic reticulum = stress-response=20 element (ERSE), unfolded protein response element (UPRE), and a = second=20 type of ERSE (ERSE-II) (Yamamoto=20 et al, 2004). We tested the ability of I3C, genistein, = and=20 BRCA1 to stimulate reporters driven by the wild-type ERSE = (ERSEwt-Luc), a=20 mutant ERSE (ERSEmut-Luc, a negative control), and the ERSE-II = element=20 (ERSEII3x-Luc). Figure=20 9A shows the ability of I3C and/or=20 tunicamycin to induce ERSE signalling in T47D and MCF-7 cells. = Each agent=20 caused a significant induction of ERSEwt and ERSE-II activity=20 (P<0.001), but the ERSEmut-Luc reporter showed little or = no=20 activity. Similarly, low doses of genistein (0.5 and 1.0 M) significantly = activated the=20 ERSEwt and ERSE-II but not the ERSEmut reporter = (P<0.001) (Figure=20 9B). CHOP is a stress-responsive transcriptional regulator = implicated=20 in apoptosis due to severely impaired endoplasmic reticulum = function (Oyadomari=20 and Mori, 2004). Indole-3-carbinol and genistein caused = dose-dependent=20 activation of a CHOP-Luc reporter in T47D and MCF-7 cells=20 (P<0.001) (Figure=20 9C).

Figure 9
Stimulation of=20 endoplasmic reticulum stress signalling by I3C, genistein, = and=20 BRCA1. (A) Stimulation of ERSE-driven reporter = activity by=20 I3C and tunicamycin. MCF-7 or T47D cells were transfected = overnight=20 with the indicated luciferase reporter, washed, = postincubated with=20 tunicamycin (1 g/ml) and/or I3C (100 M) for 24-h, = and harvested=20 for luciferase assays. Luciferase activity was expressed = relative to=20 that observed using the ERSEwt-Luc reporter in the absence = of=20 tunicamycin or I3C. Values are means=B1s.e.m.'s of four replicate wells. = The reporters=20 tested were driven by the wt endoplasmic reticulum = stress-response=20 element (ERSEwt-Luc), a mutant ERSE (ERSEmut-Luc), and three = copies=20 of the ERSE-II element (ERSEII3x-Luc). (B) = Stimulation of=20 ERSE reporter activity by genistein. Assays were performed = as above,=20 except that after transfection of reporters, the cells were = treated=20 with genistein (0.5 or 1.0 M) for 24 h. = (C)=20 Stimulation of CHOP promoter-reporter=20 activity by I3C and gensitein. Cells were transfected = overnight with=20 the a reporter composed of the CHOP promoter upstream of a=20 luciferase gene (pCHOP-Luc), washed, and postincubated with=20 different doses of I3C or genistein for 24 h. Luciferase = activity=20 was expressed relative to that in the absence of I3C or = genistein.=20 The values are means=B1s.e.m.'s = of four=20 replicate wells. (D) Dependence of basal ERSE = reporter=20 activity on endogenous BRCA1. Proliferating cells were = pretreated=20 with BRCA1-siRNA, control-siRNA (50 nM =B4 72-h), or no siRNA (vehicle only). = After 48 h=20 of siRNA treatment, they were transfected with the indicated = ERSE=20 reporter. After siRNA treatment and transfection, the cells = were=20 washed, postincubated for 24 h, and harvested for luciferase = assays.=20 Values are expressed relative to the ERSEwt-Luc control (no = siRNA)=20 and are means=B1s.e.m.'s of four = replicate=20 wells. (E) Stimulation of ERSE reporter activity by = wtBRCA1.=20 Cells were cotransfected overnight with wtBRCA1, empty = pcDNA3=20 vector, or no vector (vehicle only) and the indicated = reporter. The=20 cells were washed and postincubated for 24 h. Luciferase = values are=20 expressed relative to the ERSEwt-Luc reporter in the absence = of=20 wtBRCA1 or pcDNA3 and are means=B1s.e.m.' of=20 quadruplicate wells. (F) Dependence of I3C-stimulated = ERSE=20 activity on endogenous BRCA1. Assays were performed as = described in=20 (D), except that after siRNA treatment and = transfection, the=20 cells were postincubated for 24 h in the absence or presence = of I3C=20 (100 M). (G) = Dependence=20 of genistein-stimulated ERSE activity on endogenous BRCA1. = Assays=20 were performed as described in (F), except using = genistein (1=20 M) instead of=20 I3C.

We next=20 found that BRCA1 (but not control) siRNA inhibited basal ERSEwt = and=20 ERSE-II reporter activity (P<0.001) (Figure=20 9D), whereas wtBRCA1 (but not empty pcDNA3 vector) enhanced = basal=20 ERSEwt and ERSE-II signalling (P<0.001) Figure=20 9E). Pretreatment with BRCA1-siRNA severely attenuated the = ability of=20 I3C to upregulate ERSEwt and ERSE-II reporter activity in T47D and = MCF-7=20 cells (P<0.001) (Figure=20 9F). Finally, pretreatment with BRCA1 (but not control) siRNA, = blocked=20 the ability of genistein to stimulate ERSEwt and ERSE-II activity=20 (P<0.001) (Figure=20 9G). These findings suggest that both I3C and genistein = stimulate ERSE=20 activity and BRCA1 is required for I3C- and genistein-induced ERSE = activity.

3D""=20

DISCUSSION

We showed that two phytochemicals with potential = cancer=20 prevention activity, I3C and genistein, each upregulate expression = of the=20 BRCA1 and BRCA2 breast cancer genes. Significant increases in = BRCA1 and=20 BRCA2 protein levels (>2-fold) were observed at relatively low = doses of=20 these agents (20 M of I3C and 0.5-1 M of genistein), = suggesting=20 potential physiologic relevance of these findings. While I3C and = genistein=20 have a variety of cellular actions in vitro and protect = against=20 various types of cancer in vivo, it is unclear which of = these=20 actions is essential for cancer prevention and to what degree. = BRCA1 and=20 BRCA2 have been identified as tumour suppressors for several = different=20 hormone-responsive cancer types (breast and prostate cancers = (BRCA1 and=20 BRCA2) and endometrial and cervical cancer (BRCA1)) and a = non-endocrine=20 cancer type (pancreas cancer (BRCA1 and BRCA2)) (Struewing=20 et al, 1997; Thompson=20 and Easton, 2002; Aretini=20 et al, 2003; Edwards=20 et al, 2003). Thus, it is plausible to hypothesise that = some of=20 the chemoprevention activity of I3C and genistein is due to = stimulation of=20 BRCA expression.

Evidence of = a role for=20 BRCA1 in sporadic mammary carcinogenesis supports this idea. Thus, = BRCA1=20 expression is decreased or absent in a significant proportion of = sporadic=20 breast and ovarian cancer cases, in part because of = hypermethylation of=20 the BRCA1 promoter on CpG islands (Wilson=20 et al, 1999; Rice=20 et al, 2000). A significant fraction of sporadic breast = cancers=20 (46%) were found to be haploinsufficient for BRCA1 (Staff=20 et al, 2003). Moreover, several agents that may = contribute to=20 breast cancer development (polycyclic aromatic hydrocarbons (e.g., = benzo(a)pyrene) and alcohol) downregulate BRCA1 expression (Fan=20 et al, 2000; Jeffy=20 et al, 2002). While the loss of BRCA1 expression or = function is=20 linked to breast cancer, the role of upregulation of either BRCA = gene in=20 preventing cancer is unclear. Several studies suggest that BRCA = expression=20 is strongly induced in proliferating cells undergoing = differentiation,=20 including those in the mammary gland during puberty and pregnancy = (Rajan=20 et al, 1996, 1997;=20 Bernard-Gallon=20 et al, 2001). These findings suggest that the BRCA = genes are=20 highly induced and play anticarcinogenic roles at specific times = during=20 mammary development. If so, then agents that upregulate BRCA1 and = BRCA2 in=20 mammary epithelial cells may prevent cancer=20 development.

Genistein has = multiple=20 biologic actions, some of which may contribute to its cancer = prevention=20 activity: (1) inhibition of hormone-dependent and -independent = cancer cell=20 proliferation, antiapoptotic signalling (NF-B and c-Akt), toposomerase II activity, tyrosine kinase activity, = and=20 angiogenesis; and (2) stimulation of TGF- signal transduction, p53 and Chk2 = kinase=20 activity, antioxidant activity, and differentiation (Castle=20 and Thrasher, 2002; Sarkar=20 and Li, 2002). Our findings indicate that genistein = upregulates BRCA1=20 and BRCA2 expression in breast and prostate cancer cell lines. In = a=20 previous study, genistein caused an increase in BRCA2 mRNA (but = not=20 protein) levels in MDA-MB-231 and MCF-10A but not in MCF-7 cells = (Vissac-Sabatier=20 et al, 2003). In that study, daidzein, another soy = isoflavone,=20 had no effect on BRCA2 expression. There were methodologic = differences=20 between that study and ours (e.g., the use of affinity = chromatography to=20 measure BRCA2 protein). Nonetheless, the reason for the = differences with=20 our results are unclear, since we found that the BRCA2 protein was = highly=20 induced in a reproducible fashion in four different human cancer = cell=20 lines.

Several factors = suggest that=20 BRCA induction by phytochemicals is not due to ER- signalling: (1) the BRCA genes were = induced=20 equally by I3C and genisein in MCF-7 cells treated without = vs with=20 ICI182,780 (which causes degradation of ER-); (2) another anti-oestrogen, = Tamoxifen, had no=20 effect on BRCA1 levels (Jones=20 et al, 2005); (3) BRCA1 and BRCA2 were strongly induced = by I3C=20 and genistein in ER--negative DU-145 prostate cancer = cells; and (4)=20 I3C upregulates BRCA1 expression in ER- negative breast cancer (MDA-MB-231 = and=20 MDA-MB-468) and cervical cancer cells or human foreskin = keratinocytes (Meng=20 et al, 2000a 2000b,=20 2001;=20 Carter=20 et al, 2002). Finally, our results suggest induction of = BRCA=20 expression by an oestrogen-independent mechanism involving an = endoplasmic=20 reticulum stress-like response.

We=20 showed some activities of I3C and genistein are blocked or = partially=20 reversed by inhibition of BRCA1: (1) upregulation of BRCA2 by I3C = or=20 genistein; (2) cytotoxicity due to high doses of I3C; (3) = inhibition of=20 E2-stimulated ER- activity by I3C and/or=20 genistein in breast cancer cells; and (4) inhibition of = DHT-stimulated AR=20 activity by I3C and genistein in prostate cancer cells. Studies = using=20 under- and overexpression of BRCA1 and BRCA2 suggest that the = ability of=20 BRCA1 to modulate I3C cytotoxicity is due, in part, to BRCA2. On = the other=20 hand, the I3C inhibition of ER- activity is due mostly to BRCA1, = and not BRCA2.=20 Indole-3carbinol and genistein may exert BRCA1-dependent and=20 BRCA1-independent effects on ER- and AR signalling, since = BRCA1-siRNA can=20 influence ER- and AR activity in the absence of=20 phytochemicals. It is also noteworthy that some of the effects of=20 genistein on oestrogen receptor signalling may be mediated through = ER-, since genistein has a higher = affinity for=20 ER- than for ER- (Kuiper=20 et al, 1998).

Rescue of the=20 inhibition of ER- by I3C and/or=20 genistein is consistent with previous studies showing that wtBRCA1 = inhibits ER- signalling and a DN-BRCA1 rescues = the=20 inhibition (Fan=20 et al, 1999b; 2001a,=20 2001b).=20 However, the finding that BRCA1-siRNA stimulates AR activity and = partially=20 reverses the inhibition of DHT-induced AR activity by I3C and = genistein is=20 somewhat surprising, since wtBRCA1 and wtBRCA2 were reported to = stimulate=20 AR signalling (Yeh=20 et al, 2000; Shin=20 and Verma, 2003). Presently, we do not have a good explanation = for=20 this discrepancy; but we have observed that wtBRCA1 either has no = effect=20 on or modestly enhances DHT-stimulated activation of several = ARE-driven=20 reporters (ARE-TK-Luc and MMTV-Luc) (unpublished results), = suggesting that=20 the consequences of underexpressing BRCA1 may not be predictable = based on=20 overexpression models. Interestingly, treatment of LNCaP cells = with=20 BRCA1-siRNA plus DHT caused an increase in AR protein, which may = have=20 contributed to the increase in DHT-stimulated AR activity in cells = treated=20 with BRCA1-siRNA. The increase in AR protein was not due to an = increase in=20 mRNA but was associated with a slight decrease in electrophoretic=20 mobility, consistent with post-translation modification (e.g.,=20 phosphorylation). Since the cofactor environment is critical to AR = activity, it is also possible that loss of BRCA1 causes = upregulation of an=20 AR coactivator(s) and/or downregulation = of an AR=20 corepressor(s).

In a recent = study, it=20 was reported that prepubertal exposure of rats (age 7-20 days) to genistein caused prolonged = upregulation of=20 BRCA1 mRNA expression in the mammary glands (Cabanes=20 et al, 2004). The induction of BRCA1 was associated = with=20 morphologic evidence of mammary differentiation and a reduced=20 susceptibility to 7,12-dimethylbenz[a]anthracene-induced mammary tumours. These = findings=20 suggest that BRCA1 may contribute to protection against mammary=20 tumorigenesis by genistein, but cause and effect have not yet been = proven.

Taken together, our = findings=20 suggest that BRCA1 and BRCA2 are potential molecular targets for = the=20 chemoprevention agents I3C and genistein. Although we did not = extensively=20 study combinations of agents, our findings suggest that I3C and = genistein=20 may act synergistically or supra-additively to stimulate BRCA1 and = BRCA2=20 expression. Further work is required to determine if BRCA1 and = BRCA2 are=20 potential intermediate biomarkers that predict the efficacy of = these or=20 other prevention agents and whether a combination of I3C and = genistein can=20 provide greater cancer prevention efficacy with the same or less = toxicity=20 (i.e., a better therapeutic ratio).

Our=20 studies suggest that I3C induces BRCA expression via an = endoplasmic=20 reticulum stress-like pathway, although this hypothesis needs to = be=20 definitively proved. A previous study revealed that the I3C = metabolite DIM=20 activates multiple endoplasmic reticulum stress pathways, leading = to=20 induction of downstream target genes (e.g., chaperones) and = activation of=20 c-Jun N-terminal kinases JNK1 and JNK2 (Sun=20 et al, 2004). Here, we found that I3C activates ERSE = and=20 ERSE-II signalling and induces CHOP promoter activity in T47D and = MCF-7=20 cells, consistent with an endoplasmic reticulum stress-like = response.=20 Importantly, two agents known to cause endoplasmic reticulum = stress,=20 thapsigargin and tunicamycin, also induced BRCA1 and BRCA2 = expression; and=20 a DN PERK, an upstream component of endoplasmic and nutritional=20 stress-response pathways, blocked I3C-induced BRCA1=20 expression.

The mechanism(s) = by which=20 endoplasmic reticulum signalling induces BRCA1 expression remains = to be=20 determined. We analysed the BRCA1 promoter sequence (GeneBank=20 Accession U37574) for canonical ERSE (ccaat-n9-ccacg), UPRE=20 (tgacgtgg/a), and = ERSE-II(attgg-n-ccacg)=20 elements (where n=3Dany nucleotide). The 1.5-kb region = upstream of=20 the BRCA1-coding sequence did not contain any complete ERSE or = ERSE-II=20 elements, but it did contain a number of half-sites. However, this = region=20 does contain two possible UPREs: tgacgtga and tggcgtgg. The role = of these=20 elements in mediating phytochemical induction of BRCA1 remains to = be=20 determined.

Our results also = suggest a=20 role for BRCA1 in endoplasmic reticulum stress signalling, since = BRCA1 was=20 found to positively regulate ERSE and ERSE-II activity. Thus, = knockdown of=20 BRCA1 inhibited basal ERSE and ERSE-II activity, while = overexpression of=20 BRCA1 stimulated ERSE and ERSE-II activity; and knockdown of BRCA1 = reduced=20 the I3C-induced ERSE and ERSE-II activity. These results are = consistent=20 with a model in which BRCA1 is both a target and a mediator of the = endoplasmic reticulum stress response, as are other = transcriptional=20 regulators, such as activating transcription factor 6 (ATF6) and X = box-binding protein 1 (XBP1). Finally, we found that low doses of=20 genistein (0.5-1.0 M) significantly = induced ERSE,=20 ERSE-II, and CHOP promoter activity, suggesting that genistein can = activate endoplasmic reticulum stress response signalling, = although the=20 extent of the pathway activated and its significance remain to be=20 determined. The ability of genistein to induce endoplasmic = reticulum=20 stress response signalling could, in part, explain how low doses = of=20 genistein induce BRCA gene expression.

3D""

Acknowledgements

This=20 research was supported, in part, by United States Public Health = Service=20 Grants R01-CA104546, R01-CA82599, R01-CA80000, RO1-ES09169 (to = EMR),=20 R21-AA13122 (to SF), and by a grant from the Susan G Komen Breast = Cancer=20 Foundation (BCTR0201295) to EMR.

REFERENCES

Andres JL, = Fan S, Turkel=20 GJ, Wang JA, Twu NF, Yuan RQ, Lamszus K, Goldberg ID, Rosen EM = (1998)=20 Regulation of BRCA1 and BRCA2 expression in human breast cancer = cells by=20 DNA-damaging agents. Oncogene 16: 2229=962241 | Article | PubMed | ISI | ChemPort |

Aretini P, D'Andrea E, Pasini = B, Viel A,=20 Costantini RM, Cortesi L, Ricevuto E, Agata S, Bisegna R, Boiocchi = M,=20 Caligo MA, Chieco-Bianchi L, Cipollini G, Crucianelli R, D'Amico = C,=20 Federico M, Ghimenti C, De Giacomi C, De Nicolo A, Della Puppa L, = Ferrari=20 S, Ficorella C, Iandolo D, Manoukian S, Marchetti P, Marroni F, = Menin C,=20 Montagna M, Ottini L, Pensotti V, Pierotti M, Radice P, Santarosa = M,=20 Silingardi V, Turchetti D, Bevilacqua G, Presciuttini S (2003) = Different=20 expressivity of BRCA1 and BRCA2: analysis of 179 Italian pedigrees = with=20 identified mutation. Breast Cancer Res = Treat=20 81: 71=9679 | Article | PubMed | ISI | ChemPort |

Bell MC, Crowley-Nowick P, = Bradlow HL,=20 Sepkovic DW, Schmidt-Grimminger D, Howell P, Mayeaux EJ, Tucker A, = Turbat-Herrera EA, Mathis JM (2000) Placebo-controlled trial of=20 indole-3-carbinol in the treatment of CIN. Gynecol=20 Oncol 78: = 123=96129 | Article | PubMed | ISI | ChemPort |

Bernard-Gallon DJ, De Latour = MP, Sylvain=20 V, Vissac C, Aunoble B, Chassagne J, Bignon YJ (2001) Brca1 and = Brca2=20 protein expression patterns in different tissues of murine origin. = Int J Oncol 18:=20 271=96280 | PubMed | ISI | ChemPort |

Bonnesen C, Eggleston IM, = Hayes JD (2001)=20 Dietary indoles and isothiocyanates that are generated from = cruciferous=20 vegetables can both stimulate apoptosis and confer protection = against DNA=20 damage in human colon cell lines. Cancer = Res=20 61: 6120=966130 | PubMed | ISI | ChemPort |

Bradlow HL, Michnovicz J, = Telang NT,=20 Osborne MP (1991) Effects of dietary indole-3-carbinol on = estradiol=20 metabolism and spontaneous mammary tumors in mice. Carcinogenesis 12:=20 1571=961574 | PubMed | ISI | ChemPort |

Bruhat A, Jousse C, Carraro V, = Reimold AM,=20 Ferrara M, Fafournoux P (2000) Amino acids control mammalian gene=20 transcription: activating transcription factor 2 is essential for = the=20 amino acid responsiveness of the CHOP promoter. Mol=20 Cell Biol 20: = 7192=967204 | Article | PubMed | ISI | ChemPort |

Cabanes A, Wang M, Olivo S, = DeAssis S,=20 Gustafsson JA, Khan G, Hilakivi-Clarke L (2004) Prepubertal = estradiol and=20 genistein exposures up-regulate BRCA1 mRNA and reduce mammary=20 tumorigenesis. Carcinogenesis 25: 741=96748 | PubMed | ISI | ChemPort |

Carter TH, Liu K, Ralph Jr W, = Chen D, Qi=20 M, Fan S, Yuan F, Rosen EM, Auborn KJ (2002) Diindolylmethane = alters gene=20 expression in human keratinocytes. J = Nutr 132: 3314=963324 | PubMed | ISI | ChemPort |

Castle EP, Thrasher JB = (2002) The role=20 of soy phytoestrogens in prostate cancer. Urol Clin=20 North Am 29: = 71=9681 | Article | PubMed | ISI |

Chen D-Z, Mei Q, Auborn KJ, = Carter TH=20 (2001) Indole-3-carbinol and diindolylmethane induce apoptosis of = human=20 cervical cancer cells and in murine HPV16-transgenic preneoplastic = cervical epithelium. J Nutr 131: 3294=963302 | PubMed | ISI | ChemPort |

Chen I, McDougal A, Wang F, = Safe S=20 (1998) Aryl hydrocarbon-mediated antiestrogenic and = antitumorigenic=20 activity of diindolymethane. Carcinogenesis=20 19: 1631=961639 | Article | PubMed | ISI | ChemPort |

Chinni SR, Li Y, Upadhyay S, = Koppolu PK,=20 Sarkar FH (2001) Indole-3-carbinol (I3C) induced cell growth = inhibition,=20 G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene 20:=20 2927=962936 | Article | PubMed | ISI | ChemPort |

Cover CM, Hsieh SJ, Cram EJ, = Hong C,=20 Riby JE, Bjeldanes LF, Firestone GL (1999) Indole-3-carbinol and = tamoxifen=20 cooperate to arrest the cell cycle of MCF-7 human breast cancer = cells.=20 Cancer Res 59:=20 1244=961251 | PubMed | ISI | ChemPort |

Cover CM, Hsieh SJ, Tran SH, = Hallden G,=20 Kim GS, Bjeldanes LF, Firestone GL (1998) Indole-3-carbinol = inhibits the=20 expression of cyclin-dependent kinase-6 and induces a G1 cell = cycle arrest=20 of human breast cancer cells independent of estrogen receptor = signaling.=20 J Biol Chem 273:=20 3838=963847 | Article | PubMed | ISI | ChemPort |

Edwards SM, Kote-Jarai Z, = Meitz J,=20 Hamoudi R, Hope Q, Osin P, Jackson R, Southgate C, Singh R, = Falconer A,=20 Dearnaley DP, Ardern-Jones A, Murkin A, Dowe A, Kelly J, Williams = S, Oram=20 R, Stevens M, Teare DM, Ponder BA, Gayther SA, Easton DF, Eeles = RA, Cancer=20 Research UK/Bristish Prostate Group UK Familial Prostate Cancer = Study=20 Collaborators; British Association of Urological Surgeons Section = of=20 Oncology (2003) Two percent of men with early-onset prostate = cancer harbor=20 germline mutations in the BRCA2 gene. Am J = Hum=20 Genet 1: 1=9612 | Article |

Fan S, Ma YX, Wang C, Yuan = RQ, Meng Q,=20 Wang JA, Erdos M, Goldberg ID, Webb P, Kushner PJ, Pestell RG, = Rosen EM=20 (2001a) Role of direct interaction in BRCA1 inhibition of estrogen = receptor activity. Oncogene 20: 77=9687 | Article | PubMed | ISI | ChemPort |

Fan S, Meng Q, Gao B, = Grossman J,=20 Yadegari M, Goldberg ID, Rosen EM (2000) Alcohol stimulates = estrogen=20 receptor signaling in human breast cancer cell lines. Cancer Res 60: = 5635=965639 | PubMed | ISI | ChemPort |

Fan S, Wang JA, Yuan RQ, = Goldberg ID,=20 Rosen EM (1999a) Co-ordinate down-regulation of BRCA1, BRCA2, = Rad51, and=20 p300 during the response to damage in human prostate cancer cell = lines.=20 Prostate 40:=20 37=9649 | ISI |

Fan S, Wang JA, Yuan RQ, Ma = YX, Meng Q,=20 Erdos MR, Brody LC, Goldberg ID, Rosen EM (1998) BRCA1 as a human = prostate=20 tumor suppressor: Modulation of proliferation, damage responses, = and=20 expression of cell regulatory proteins. Oncogene 16:=20 3069=963083 | Article | PubMed | ISI | ChemPort |

Fan S, Wang J, Yuan R, Ma Y, = Meng Q,=20 Erdos MR, Pestell RG, Yuan F, Auborn KJ, Goldberg ID, Rosen EM = (1999b)=20 BRCA1 inhibits estrogen receptor signaling in transfected cells. = Science 284:=20 1354=961356 | Article | PubMed | ISI | ChemPort |

Fan S, Yuan RQ, Ma YX, Meng = Q, Goldberg=20 ID, Rosen EM (2001b) Mutant BRCA1 genes antagonize phenotype of = wild-type=20 BRCA1. Oncogene 20:=20 8215=968235 | Article | PubMed | ISI | ChemPort |

Graham S, Marshall J, = Mettlin C, Rzepka=20 T, Nemoto T, Byers T (1982) Diet in the epidemiology of breast = cancer.=20 Am J Epidemiol 116:=20 68=9675 | PubMed | ISI | ChemPort |

Hayes JD, McMahon M (2001) = Molecular=20 basis for the contribution of the antioxidant responsive element = to cancer=20 chemoprevention. Review. Cancer Lett = 174: 103=96113 | Article | PubMed | ISI | ChemPort |

Jeffy BD, Chirnomas RB, Chen = EJ, Gudas=20 JM, Romagnolo DF (2002) Activation of the aromatic hydrocarbon = receptor=20 pathway is not sufficient for transcriptional repression of = BRCA-1:=20 requirements for metabolism of benzo[a]pyrene to=20 7r,8t-dihydroxy-9t,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. = Cancer Res 62: = 113=96121 | PubMed | ISI | ChemPort |

Jin L, Qi M, Chen DZ, = Anderson A, Yang=20 GY, Arbeit JM, Auborn KJ (1999) Indole-3-carbinol prevents = cervical cancer=20 in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res 59: = 3991=963997 | PubMed | ISI | ChemPort |

Jones LP, Li M, Halama ED, = Ma Y, Lubet=20 R, Grubbs CJ, Deng CX, Rosen EM, Furth PA (2005) Promotion of = mammary=20 cancer development by tamoxifen in a mouse model of = Brca1-mutation-related=20 breast cancer. Oncogene 24: 3554=963562 | Article | PubMed | ISI | ChemPort |

Kojima T, Tanaka T, Mori H = (1994)=20 Chemoprevention of spontaneous endometrial cancer in female donryu = rats by=20 indole-3-carbinol. Cancer Res 54: 1446=961449 | PubMed | ISI | ChemPort |

Kuiper GG, Lemmen JG, = Carlsson B, Corton=20 JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA (1998) = Interaction of estrogenic chemicals and phytoestrogens with = estrogen=20 receptor beta. Endocrinology 139: 4252=964263 | Article | PubMed | ISI | ChemPort |

Kwak MK, Itoh K, Yamamoto M, = Kensler TW=20 (2002) Enhanced expression of the transcription factor Nrf2 by = cancer=20 chemopreventive agents: role of antioxidant response element-like=20 sequences in the nrf2 promoter. Mol Cell = Biol=20 22: 2883=962892 | Article | PubMed | ISI | ChemPort |

Lamartiniere CA, Cotroneo = MS, Fritz WA,=20 Wang J, Mentor-Marcel R, Elgavish A (2002) Genistein = chemoprevention:=20 timing and mechanisms of action in murine mammary and prostate = tumors.=20 J Nutr 132:=20 552S=96558S | PubMed | ISI |

Le HT, Schaldach CM, = Firestone GL,=20 Bjeldanes JF (2003) Plant derived 3,3'-diindolylmethane is a = strong=20 androgen antagonist in human prostate cancer cells. J=20 Biol Chem 278:=20 21136=9621145 | Article | PubMed | ISI | ChemPort |

Maggiolini M, Vivacqua A, = Carpino A,=20 Bonofiglio D, Fasanella G, Salerno M, Picard D, Ando S (2002) The = mutant=20 androgen receptor T877A mediates the proliferative but not the = cytotoxic=20 dose-dependent effects of genistein and quercetin on human LNCaP = prostate=20 cancer cells. Mol Pharmacol 62: 1027=961035 | Article | PubMed | ISI | ChemPort |

Meng Q, Goldberg ID, Rosen = EM, Fan S=20 (2001) Inhibitory effects of indole-3-carbinol on invasion and = migration=20 in human breast cancer cells. Breast Cancer = Res=20 Treat 63: = 147=96152 | ISI |

Meng Q, Qi M, Chen DZ, Yuan = R, Goldberg=20 ID, Rosen EM, Auborn K, Fan S (2000a) Suppression of breast cancer = invasion and migration mediated by indole-3-carbinol: associated = with=20 up-regulation of BRCA1 and E-cadherin/catenin complexes. J Mol Med 78:=20 155=96165 | Article | PubMed | ISI | ChemPort |

Meng Q, Yuan F, Goldberg ID, = Rosen EM,=20 Auborn K, Fan S (2000b) Indole-3-carbinol is a negative regulator = of=20 estrogen receptor- signaling in human tumor cells. = J Nutr 130:=20 2927=962931 | ISI | ChemPort |

Mentor-Marcel R, = Lamartiniere CA,=20 Greenberg NM, Elagavish A (2001) Genistein in the diet reduces the = incidence of prostate tumors in a transgenic mouse (TRAMP). Cancer Res 61: = 6777=966782 | PubMed | ISI | ChemPort |

Michnovicz JJ, Bradlow HL = (1990)=20 Induction of estradiol metabolism by dietary indole-3-carbinol in = humans.=20 J Natl Cancer Inst 82: 947=96949 | PubMed | ChemPort |

Nacheson-Kedmi M, Yannai S, = Haj A, Fares=20 FA (2003) Indole-3-carbinol and 3,3'-diindolylmethane induce = apoptosis in=20 human prostate cancer cells. Food Chem = Toxicol=20 41: 745=96752 | PubMed |

Oyadomari S, Mori M (2004) = Roles of=20 CHOP/GADD153 in endoplasmic reticulum stress. Cell=20 Death Differ 11: 381=96389,=20 Review | Article | PubMed | ISI | ChemPort |

Page KM, Heblich F, Davies = A, Butcher=20 AJ, Leroy J, Bertaso F, Pratt WS, Dolphin AC (2004) = Dominant-negative=20 calcium channel suppression by truncated constructs involves a = kinase=20 implicated in the unfolded protein response. J=20 Neurosci 24: = 5400=965409 | Article | PubMed | ISI | ChemPort |

Rahman KM, Aranha O, Sarkar = FH (2003)=20 Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not = in=20 nontumorigenic breast epithelial cells. Nutr = Cancer 45: = 101=96112 | PubMed | ISI | ChemPort |

Rajan JV, Marquis ST, = Gardner HP,=20 Chodosh LA (1997) Developmental expression of Brca2 colocalizes = with Brca1=20 and is associated with proliferation and differentiation in = multiple=20 tissues. Dev Biol 184: 385=96401 | Article | PubMed | ISI | ChemPort |

Rajan JV, Wang M, Marquis = ST, Chodosh LA=20 (1996) Brca2 is coordinately regulated with Brca1 during = proliferation and=20 differentiation in mammary epithelial cells. Proc Natl=20 Acad Sci USA 93:=20 13078=9613083 | Article | PubMed | ChemPort |

Rice JC, Ozcelik H, Maxeiner = P, Andrulis=20 I, Futscher BW (2000) Methylation of the BRCA1 promoter is = associated with=20 decreased BRCA1 mRNA levels in clinical breast cancer specimens. = Carcinogenesis 21:=20 1761=961765 | Article | PubMed | ISI | ChemPort |

Rosen CA, Woodson GE, = Thompson JW,=20 Hengesteg AP, Bradlow HL (1998) Preliminary results of the use of=20 indole-3-carbinol for recurrent laryngeal papillomatosis. Otolaryngol Head Neck Surg 118: 810=96815 | Article | PubMed | ISI | ChemPort |

Roybal CN, Yang S, Sun CW, = Hurtado D,=20 Vander Jagt DL, Townes TM, Abcouwer SF (2004) Homocysteine = increases the=20 expression of vascular endothelial growth factor by a mechanism = involving=20 endoplasmic reticulum stress and transcription factor ATF4. J Biol Chem 279:=20 14844=9614852 | Article | PubMed | ISI | ChemPort |

Rutkowski DT, Kaufman RJ = (2003) All=20 roads lead to ATF4. Dev Cell 4: 442=96444, Review | Article | PubMed | ISI | ChemPort |

Sarkar FH, Li Y (2002) = Mechanisms of=20 cancer chemoprevention by soy isoflavone genistein. Cancer Metast Rev 21:=20 265=96280 | Article | ISI | ChemPort |

Sarkar FH, Rahman KM, Li Y = (2003) Bax=20 translocation to mitochondria is an important event in inducing = apoptotic=20 cell death by indole-3-carbinol (I3C) treatment of breast cancer = cells.=20 J Nutr 133:=20 2434S=962439S | PubMed | ISI | ChemPort |

Shen X, Ellis RE, Lee K, Liu = CY, Yang K,=20 Solomon A, Yoshida H, Morimoto R, Kurnit DM, Mori K, Kaufman RJ = (2001)=20 Complementary signaling pathways regulate the unfolded protein = response=20 and are required for C. elegans development. Cell 107:=20 893=96903 | Article | PubMed | ISI | ChemPort |

Shin S, Verma IM (2003) = BRCA2 cooperates=20 with histone acetyltransferases in androgen receptor-mediated=20 transcription. Proc Natl Acad Sci USA = 100: 7201=967206 | Article | PubMed | ChemPort |

Staff S, Isola J, Tanner M = (2003)=20 Haplo-insufficiency of BRCA1 in sporadic breast cancer. Cancer Res 63: = 4978=964983 | PubMed | ISI | ChemPort |

Struewing JP, Hartge P, = Wacholder S,=20 Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA = (1997)=20 The risk of cancer associated with specific mutations of BRCA1 and = BRCA2=20 among Ashkenazi Jews. N Engl J Med = 336: 1401=961408 | Article | PubMed | ISI | ChemPort |

Sun S, Han J, Ralph Jr WM,=20 Chandrasekaran A, Liu K, Auborn KJ, Carter TH (2004) Endoplasmic = reticulum=20 stress as a correlate of cytotoxicity in human tumor cells exposed = to=20 diindolylmethane in vitro. Cell = Stress=20 Chaperones 9: = 76=9687 | 2.0.CO;2= "=20 target=3Dexternal>Article | PubMed | ISI | ChemPort |

Thompson D, Easton DF, = Breast Cancer=20 Linkage Consortium (2002) Cancer incidence in BRCA1 mutation = carriers.=20 J Natl Cancer Inst 94: 1358=961365 | Article | PubMed | ChemPort |

Vissac-Sabatier C, Bignon = YJ,=20 Bernard-Gallon DJ (2003) Effects of the phytoestrogens genistein = and=20 daidzein on BRCA2 tumor suppressor gene expression in breast cell = lines.=20 Nutr Cancer 45:=20 247=96255 | PubMed | ISI | ChemPort |

Wang TT, Sathyamoorthy N, = Phang JM=20 (1996) Molecular effects of genistein on estrogen receptor = mediated=20 pathways. Carcinogenesis 17: 271=96275 | PubMed | ISI | ChemPort |

Wang XZ, Harding HP, Zhang = Y, Jolicoeur=20 EM, Kuroda M, Ron D (1998) Cloning of mammalian Ire1 reveals = diversity in=20 the ER stress responses. EMBO J 17: 5708=965817 | Article | PubMed | ISI | ChemPort |

Wilson CA, Ramos L, = Villasenor MR,=20 Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, = Livingston D,=20 Zuch RH, Kanter MH, Cohen S, Calzone FJ, Slamon DJ (1999) = Localization of=20 human BRCA1 and its loss in high-grade, non-inherited breast = carcinomas.=20 Nat Genet 21:=20 236=96340 | Article | PubMed | ISI | ChemPort |

Xiong J, Fan S, Meng Q, = Schramm L, Wang=20 C, Bouzahza B, Zhou J, Zafonte B, Goldberg ID, Haddad BR, Pestell = RG,=20 Rosen EM (2003) BRCA1 inhibition of telomerase activity in = cultured cells.=20 Mol Cell Biol 23:=20 8668=968690 | Article | PubMed | ISI | ChemPort |

Yamamoto K, Yoshida H, = Kokame K, Kaufman=20 RJ, Mori K (2004) Differential contributions of ATF6 and XBP1 to = the=20 activation of endoplasmic reticulum stress-responsive = cis-acting=20 elements ERSE, UPRE and ERSE-II. J Biochem=20 (Tokyo) 136: = 343=96350 | PubMed | ChemPort |

Yeh S, Hu YC, Rahman M, Lin = HK, Hsu CL,=20 Ting HJ, Kang HY, Chang C (2000) Increase of androgen-induced cell = death=20 and androgen receptor transactivation by BRCA1 in prostate cancer = cells.=20 Proc Natl Acad Sci USA 97: 11256=9611261 | Article | PubMed | ChemPort |

Yoshida H, Haze K, Yanagi H, = Yura T,=20 Mori K (1998) Identification of the cis-acting endoplasmic=20 reticulum stress response element responsible for transcriptional=20 induction of mammalian glucose-regulated proteins. J=20 Biol Chem 273:=20 33741=9633749 | Article | PubMed | ISI | ChemPort |

= back=20 to top 3D""=20

	Article = links


		Send to a friend
		Downlo= ad=20 PDF



		Abstract
		Materials=20 And Methods
		Results
		Discussion
		References



		Prec= eding=20 article
		Next= =20 article
		Table of=20 Contents

------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/bjc_logo.gif R0lGODlhwwBVALMAADMAZv///2tGkK6awoRlo8O00pqBs04ietrR4+Ha6c3B2ufh7e3o8fTx9/Ht 9Pn3+iwAAAAAwwBVAEAE/xDISau9OOvNu/9gKI5kaZ6AQAzK0rwNgwyEgN54fg1B7/sEjODx+xUw i6IPoTkglL5jSMAI2HTY7IcA7V0the4X3B1YDsSuQctut7ldwgFwOAgMVSgjmAlDzRUOXQFSboaH J3BQYxUCgw0XfkqFFDyDc4iZmh2SSowCnUUPjBNoXZRCT4MIBphCA0lem7O0IapFCa61u7y9Jg0P dA8KAAnBEsYpVgAGVgcNAbnNNggLFc0HYXNcBFw2CQkAPJgOxFytA+kBQeUU5wBcRwyUB1WMBAUG C+HTAAEKBwJYkxBwgQo53nwpXMiwocOHECNKnHhCwaAFBdIVuFUmgykoDf90eRyQ5lQNASgJGOD4 gxTFTIo8ZbCkZKAFi1BQTaCpJNfLnxhiFkFQoCgCaD8aDHAZqWMFnkWIAZ1qQWjLDDgXNf1joVkX m1TDeoXCZyvZCyyjZLD6o2zYlwxi7ENAt9oCB8Ae6H3gIIECGh7YygpxAF+CQUoezHD7tnGpWEUM bghoxdGaCnWUBbFjgQdTbGzabVDA6ICDB5sLiHRMkUACpqxjy5Zdt7bt27hz697Nu7fv38CDCx9O PPfs48iTKzeUB7HzpRsED/4gAKrzSXKW47AO5MJYJQwyIO3JQYCgLghWXyBQUqd2Et+LMKYQyscD 9Wl7uJfgqIsD9R4A+J7/CNLBlt8yZhUBSCOICTjgJgVaIABkPjgwXwX19bDgBNKF9+BC0iH2wgKt cOIUBQcS8iGIg7h0AIU/3IdBhgFsKEGK+60IYYtrrZLgDzYqM8hlOu4S31VB+WjBgfvRGAADDhbZ Bnc9XAhAVkoEKcF4QzVxmH9WajBhAFFKueR116Un5iBaBtUcYnsNEo6ZEB3Zg1Q31KGnnnQCJQCX 3ZVgAJH8DSDSCrC5MQCha6l2QZlThdEAUWFeAM0KajLgwBPPkMmDatOYh88BzShgESrYHKBAAq4R 008PAISxT6cFCCJANgNoOodoE9QqQAuFPUAiBVWIZEBRNYrzzxNr/KmA/2sqrKMAE814OBVl+KwD QBKYVKGMGdOoNGF1yywAFjNkmqbaAkxwkUAYwYyzpTkBGMADC/UCMGkFCOSiAJT+4EmQRaQRQJpA BjwQEg9y/ANPAAioVBghK6CbaJ8YZ6zxxhx37PHHIIcs8sgkl2wyG+AgoEBRBZg6bb/m3sXAPisb cLEEBLBralGmVnPzBXcUAONFf/28cYpo+tAmf4PI6IEASCddZclOMgYKYoyWUlIRkHDgxCAOQBcU lgH8VzKV2l5AdlsYALrEBuYN4ujT52UNsp3TnakHBkxq4OQCkEoIcMl4I7hDF07zewoGX594MgkR zug4fZNP8OVZj5sQ+f8ZbjssOVdkoJd5IjxKGIfflfcHReKjj7A5HdwBxAGNQRbOROslhIh4xCDQ fpPcuOfeNAxbR2boBr4rvnjwrpdOwa+Ih5k8BZdPwnzzYghRvA8+hZ6l90rcfj0Irz815I9KV9V0 4OPj7LzpXXSN4fIUmKZk+x2U//wj6Ov3aOc9sBv+ujKIMBVOS30D2nlyMsANFM5KneqCeqr3A4H9 roAkAAX76IS2CxXOWhYAoAXPsEAoCPBRlshRx9YWBQN041iIsZBHtuc/rzmpBwlw4a3qkJJQmK1k Q5MaxLKzptN9oDAUFOI/jJaxzHhkT04EQeE2KKFjxWUve2lAAmhAxQb/zs6IXgyLYJgYRoUUxm0P OCHsMpIPkVBmDreymPmYMio2QIwDBOjXGEi1sox08SEUZBWkgCGBZLmQVIWRw6fqkJ0VrKEZKzge BUBDqkXxp0QqgUcN1tANROEsHVfgFYcWtY1huIVhXSFlCmyWDkxUR5WRhKPNaqGCP0JjAAkAHACY NYdkOMIG04CkBFCZy2uQqR/eSAg4lFUiGTyMSMIUpSPMwAUzOIAePVDPM6whzH/Ybw51eEB4wpWs sOhlDvtKBjKC8Us5kiqN/eiXMQ/gGYslRIvKIge97EUmbgBAmsl6xzCMuSFHEGMfFguIaoCBiWfI T45i7OQVaokzPkisRjB1GJQNKIoSDHUtkWVRSQ2CQNEU2ACjhbFZN+BRmk5iogZAGxRM77DJlGxj ohq95CwxWsae+vSnQA2qUIdK1KIa9agQiQAAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/header_right.jpg /9j/4AAQSkZJRgABAgAAZABkAAD/7AARRHVja3kAAQAEAAAALgAA/+4AIUFkb2JlAGTAAAAAAQMA EAMDBgkAAAnMAAAOAwAAGAP/2wCEAAoHBwcHBwoHBwoOCQgJDhAMCgoMEBMPDxAPDxMSDhAPDxAO EhIVFhcWFRIdHR8fHR0pKSkpKS8vLy8vLy8vLy8BCgkJCgsKDQsLDRANDg0QFA4ODg4UFw8PEQ8P Fx0VEhISEhUdGhwXFxccGiAgHR0gICgoJigoLy8vLy8vLy8vL//CABEIADgCNQMBIgACEQEDEQH/ xADUAAACAwEBAQAAAAAAAAAAAAAAAwIEBQYBBwEAAgMBAQAAAAAAAAAAAAAAAwQAAgUBBhAAAgIC AgICAgMBAQEAAAAAAQIAAxESIQQxEyIFECBBMiNCFDMRAAIBAwMDBAMAAwEAAAAAAAABESECEhAx QVFhAyAwIhNxMkKRocEjEgABAgQDBgUDBQEAAAAAAAABABEQITECQVFhIHGBoRIikTJCYgMwweHw 0fFygtITAQACAgICAQQDAQEBAAAAAAEAESExQVFhcYEQIJGhscHR8OHx/9oADAMBAAIRAxEAAAD5 cB6J4Ak9nCdat6blrJi7fM3qol5TU0Ieg1eB7po/R5O1np1a+VfiasHqvnBhY9hXZCNdrS5l4W6Y cy12tPFSInnH2XYJo+aC6u1WSda1BvUZ+vbKroiJd8PJI0Jr9z+K99LciyDJ1Xs/PT8a+s85a01t 88NUWxU5D2UpI2avrl5zd7o3899tZRsidiPpsy/eRu1tDJ+jVU0uNz+/5vFLzpeE3ucA9OyASe+x OSyJa3VcRFA3K0L9R5/bU7A1+yVttSQ+f7tR7TuJw2nnKsdB0iLrwocb2fNkczZLcBqupFrPRtK7 7grBciUqaitTM09Im9zGxyBQwv69M9aFOypAlf2wjBVlFXko1sXwtWT1evpKzWsiJUItw4uEfbAC cDdnH2S/XexfoXgytATjkqNPM0uv4zy1PsvR/HujxEtfj7nOZ5fSuDcwwPROAEgBIex9cRjL2IyR vKeyPsoZOooC1v0kK5PQ8dmcnTTX9O+bfaRP53Kdvx7Z86ndy9E0UkFqq6TB30A7PH6WJSlr2rBN x9nPfvjY/PukD02VQZYlFXsULECOUJaptGup0It30vKWj6Ay7q7tSc3FilFZ+MQr2fvnlaE4+0s/ xPvOzRIS54yJyjEyuNc1TKZn2vszmKyQkrM8D1jYBIASMtgyDxINcY4OyV8BrbNoE8XzBAWjzfTg U/a8kAtapmhokzoBhLu3A1OVsYO18kAKngK3nphrXkoCiroAF/Eh5yhaBXtf0NuaFANoctEFrUIB SL9BHi/QVp7IK2dXDtPPQTk2hSKYHIxgB6tgV5EDvf/aAAgBAgABBQH8EAxVWXr8aUUg66KTOYrB ZVksoBHOCMy07OIK2LVJpDe4Nwb9FIzyB2MFl8mU42wcV1ZmowW493NnJ/RF4txrXUoVKdF2wzcm zLufFcbgszXEKodPXFCFwMysBR2EBIOPwPJXIUN63UwJp2LXUrQG2rwKKXM3GzAMLq8DImf0Tw1e SBgEYhwzHFYGRXSZ/D7FaK9Z2lxXUmzVqEGFJC4PYIKsg9DhA9dTB4ZoFCILJ2kGqZ0Z9KUtKz2E sOzgM+Sf1rz+T4ONjiD1604yPF3t3SWT/HN+2y6/h9MfLV9c0/2nyzbtjj03RPbi+cQ6w/gzif/a AAgBAwABBQH8lNoEGucT2BoGjtmDmGOvOCJk4TOMTUYVThnZoSD+R5IOBgoPyDiYXGhjLyqjVn+N b7D9GsIi2fJ3DHOZ7GJwM/1CZzqDPTGwspZiADOcO+FA0U6spGJmKMkArMicGZ+P8HGD/bf4t4Gc spBrQgfo7EFCdSOZZw9a4I5gXMA5GksrGEXEB4ZyxbibKZj45gyZkqA+RjEOd7OID+DDzP4Iz+5g zDjMbzXtF3iz/o53ecYXafOLnUYjeWieOZZrE9kr1wM7TjP7/wD/2gAIAQEAAQUB/QeScStgJ1Go xfQLFV7aGe/2xWbartdmydP1PYesqwUL7B1hNcS0mdxwiXXeydOk2WLYKl96vCMwJAMGl9J9v2dl ALHUgYM0Jh6xxqyH23JF7AhclmGZrMQLxmZ/Cw/2ziVS0khG1awCY4/SkgsV0gqMz7IyBFVN2ZQr 166gKJ1uhi37Dr/7/wDmZV0M05/QeSuTrK3KSy5mgGx3Skv2FeL2LEP1BR4ewGY5V0uqZNnYvqy/ bX720Ue2V9VUquQ+ncqz3OJX22g7IK23tVXa5sNKCNXNcEE7WbafV9Wlp3aFUsJhjNjMiGAzExMQ CAAs8r82ef8AthwgyCIAIwGfEMrG4sJ2dAjBMoqlSSFdrUsdeqLBRSjQ/V2N2buv67b6VDa/L9cm bYnEaK0c5mjfj6nPqFYvP2FbrX0Et6h95E7lxrDHd+n13SVsZcwxdWdl0M9Ql78W9gvXT0n9Vp1v sblm+NTncuQ3WXdvsn+VdbWEprNAYyTDCBvxj8AHC8HIyoAa6YOfMUwwAGAYJ5jDC7Zl3DiewrC5 MLCIfW3U7i2rRfTXTVfV6u5cLXvsDHPz/YwCWcFc55JocqWHUtHV7Ddc09nrMvf62Kk7Gyg+2v7C 1zZ103sptFLm1YbqXHZr1nOMNpdZz0aRbe6KK+1x2TySFxSvzzmzu3f+em1m7FnX6prquU5ORG8+ QVmcQWcqcxf6hYy4iHLdkYCs2eGA4jQITBmEjL+B57KiBuCwgOSeG81Udk1MndNtdPbdqr+ycG0t Nuf2Jm02nE15qTJQHr0lKuxOpXf1Xq+5G9tddyfYXCihmZ2+l+tVet3eoliZZJaTPbmPSygK7z1s x+owh+z7H+FRBQMIXACuQQzZbaydQLTaWE7BhOYrfKwjOeODNcwZWB4gyGEqX/TtjAY4IPyZedoM j8eSv/0swHtZmJPJBLYxGwVSwpXWOarlw1pLMxzvN/8AT9m8ACawLyqxRKe8yBaKlnT7iM32XTFk v+w7ddNvYtsnW1N1bBaGBx211teWLN3UK7A5ZZ0iNO22yK2EXiMYDC0LHPlKewUl7bBYq/K0cjhc Ga8LxD5rsaqB1sFX9+9/RwCQJmfyWOB4ziAcnlnbJzOZmYzOZXwM85xGfaZ4/cDMWsRkX8DEHkqJ 1LnRupob+xcxKiu2dr6pMNTZWfrvsrAWtXHa5sdeGlrRDmDLHrr/AJWDIZGRstMibCF5UMklmGkY YmkOylhtPEWMcjyVI2FasHras13sks7i3VkCFIcg8TOTMZmMRkAY/wBj5EzVD4wYFYQAQifztNjj /9oACAECAgY/AYNdRN4Lu7rR6fyuy2748i78kTaX3Rc0CPy3Y+VPCclKgpugLRijb1HTJHps4q03 GvLYFrYK4+CtIxtmmWPFM1ZOry/8IXek0QU0Sck+0QU2auAm+aCchD4raYoACQomopHxQsFLZugA PSUJJwMEWLFpJgnOURAi6qY5DuGCtGav6TSU1bkZojUpjgunjCu27wn4prwnP+RmurH5DM7k0CJb 1dkQrWzhNPjSF4OFFadU1plnVSHUIvoye/00wXU06SVxZgbWG9WW4tDqJVPpTXBTbp91EW8v6pCa k7YdNGUqSpzQo3qddtfZ+FazoZ61gX6dXXt5cEGfihuk1NYTb7q5suan5mnmrW8rcOKFejkvj/rz QfkpPx2f/9oACAEDAgY/AY0UnFy7+m72kJukW6DYYIawKAMJrtJC6TNtkl1ajvi6BzpnAwYbYIxq myUsFyK6RlCaDwKufOOpktVSmxxTjBfZFBxNFcIOM4OOe2JQKYHY3YLHUaqqfNOgBTFMMMTANjWL ha4hSUs04xTP4ri6uOf0w0ZrghCUJ545I1r2sv8ApfsjSAZ2RhxxWui4Lu8zovTDfE79v//aAAgB AQEGPwH1dT9UXq2JIRXxqRY3Oz8MxfkbXch1Zd8Yk7k9NNjK7RPZLkwe65MdKE8H/S2xceipJR6V 0329qRFSevqaZJ9nBkSVIMWqisahsngghdBz7NGbwVK2SZYK38Ep06C8j3HbfToZx8Fu2f8Ancro 6EpU6kyYWuiJFipfYlUuW5P+yVdQrsVcGX83ci5Iu3ZubkbitsTRc/PbVKkk20tKP0x7CK6QQ9Ka SiPLRcMt8SfxIscoc1Z3Lb9y12CbLZfwSiTJL4dx28Ev2K6xpKqtE2WyoxLvHb/Soh2+Sylxi1CH 9biTuzJ1kiB9SbduhjBR06EIt8XQ+1qZLOqNjYSgVrQ09naYIhbIhjI9paP1ISF6IE0Yvci9/k/Y bt2HBPs1KadSPJZjfw0Lxx8eGePK5K67ZD8yq7al3k8lrUGdtsqNxrgttMXtBkiOR3IyMkQW5/rJ 9VmyqfhlWbiaciLLrP2J5ZtpQn2UhQVHjvyRpJUQhCvOxXVXLTKYuRvDHUfHtV1QnbF6/BOay6GV tv2fmp9fmWPA76JHwcdEiXUXk8iWV1anxhXLZohlDG4y4KaPJVQsXD7Dd1X1KVO4miWzeSfKvi+S jpx66ayioi3SSUQdtNqa2zsRrHI7epMSRsfFkt6dvd+u9ZWn32Xd4Mf8n2eJ43I+q7imR87pLMti 1W9DuPvrjwUJQ7tHb6ZRlfQwf6lPXDIWncRaT6I1yK+zOs+xX1Y/yXXbEJwNeRSmtjLwU7M+VsRy W+PyOncm0nSumxhxpjrVehW8GxsUKFSNKaVKolE7ituUPWhlyRxqoE+DsU0qfHbSpOlSh2P/2gAI AQIDAT8Q+i4FwQdb2PHca7Sh0WMGYMrH5KfqN0IYvt5gbvkmWHFd4hjjG3/IbaMgMUcj+YCsJ8zE sZVlluZ2Ho2wCFBmUsEsr5ORfwhwCjSBbj6hbtc+DEePoGTyyym3ZvWIqZuhfStRBVIINZlEu8vB bAjVDOKVGqkJpsXuJdI23ZTgjEuFHNQCgCgqEBFXx5gBnBgQCnmU/v8AX1Qdws+4VWBwsd0EGz/Z YRsuuEKhKpwM/AFmrl5LGafu5jghSmIobdy3Br8JQ5k83mU2MvvEdLDG7hoWIZMEwdcXNsq28rzc G7FAnjuIkl7xFZVWSFW8ktmWEv8AiCahroRe5fFpkPZX9Q8tUU/aoU2xkdOGBIbDBeVgcRxlgW0p 8T0TXuZJ2cxq34lP39jxgPYNa4gAdFRHaRvAzcKKCmGIb3fDYvLxKi7cfBwIrbbNkKIPJg0Oogd2 As2PJKUs5rzX+SmLcMUIByX4hpIzI3X0zCwkwe4AfOT/ADmYzLhb8pQQGm3FkKQ4nEeRl6xHNeTD 1KSjDK7V5lMQWPIeY7S2f2CPW2tupdpmysxFRZ1Ea7Z7jsvPEbj7cniY+lbcJzek+WZ7J80V1c5N dStuEyv+JZlKccPBf/Mza/L0eP3H+Q/3HRvi73zcwW9IG56adFfMM+ut/SKci6/9JOIY9d43hOGV r3lNfw3HzLXjwavKN3odzre+/wDqOGDX/fc1bfwmv0peZ8J//9oACAEDAwE/EPo3ZQL5lQsCEHhy Vf8AyN1kfAb7uLKBCwMQW+K7g2dmocKhUPmmAhbWfiAqWtQK8wQTisRJI1LHTWHUGHy3ElLHF3/X 0z9IYQU4qOgxmvLLUNgqvcprEDF4l/SjfqNgMIRWC9ksLS6jBKgxSRqvyw3IEMe5jXZKP19ebgoI IGO5dwyvSVAJZZVLwV8y8asXy13KqF7blFFN7hueTcabLNR01rnqNEemoiLQPidiWHe+GDQ5wiUr WW4r5RW/cXIz7nlD9kCs0ZXFCsRWhuGwu28sMzQ4gJhOx/cCfo/ubac/wIHlWPUW85o2xDLkxGg2 woVtcsp+xpRf7hxQjruDZRu9EBsFU77lToW1cZ7boMzcy5RMqsv5ISgVtgvgVjeeSGTgPiUNcQAL Rl1GkFb9mIhUf/ssPpb8NRVpjBcIKmSACA3XzMYV2IFNt5Y+I1Y4xKPkea/qBgpoV8upVoDaBHiD KYsH4jBTqYKBiY+aqAF3m5Ur7OW9zJlqviZ11fiNX5lL43eO5gbv+Uy0l4bYXXzc597NSle/y/8A EfOf8CYX/EcWtc8JvsOamc6uX7NmteZ0Vd/NS19Q0qu3Cb9ZY5zC/wAp3WS764npXb+ELzd3568Q 4Kv9zNbe/X0PNQ+z/9oACAEBAwE/EPs0e4ai9oB2Mxq1muoyg2MGpai6ay4iIq8kauCQ04QIOHZT a8R6vNX5jYBsWJpiGJbMCLZuEuuEolTVxXQYdS6uhG/AXTTEryhrAB3cxWrm/pp8wtgulglGbLUN Lm4VSfiW8QwqF4m+lQvGfFxJWzzGDWkjpDDzMNIIzmFzuFdvIaghuo24jrUC7lRYuCSBuYFjN4gp cblXimXA/CNr9Q7JczeZpO5ybCfqWVG2r2QoFKuogCKdSxNuiGupe4cKpWBhQGvszDgMDXcr3hlj WIIeKylRqHoU4lsvt0e5qIUNRu6psF4QU3GGBuomJlwAoBMFXRGsHdmAhp9xsVPAqi5NGbGHqGtN z0gYAptm+uNCMLF5oIPYE2nGJw7JW2oXPSOtmCtv5SygJcQoYEzswJMGgYQXUzqKQAVzFHRzUSQi 0zbW3yR7SnEAKqL3DMHBE2jXqLcUPMSviUCGrmfF+ZWPRjGZhjKCHPM0l31C5MdRL8EuFOpbJ5g5 TBMHOOpsUq2dypT0sO47nmG9w8VDgMGfMy6cfiILwI4qzzzDdyUIFZhDpkcxOw2Axb0dTC6Mirx7 qC0JTmJKX1Ofjr7TcqbGA7LirUtTcuKOSDQ5rLEyvJdEcLeHzhgQbfFcwVZ6LHytqsxmWdNoQYtc 4l9ateYzo5cvbDAHYHUsipWoi4wPzCJLtb7xDah0yx4GYUBeMSzmDRUOckwwjhaZOIRiM8S1IRYy ly1DglNiRF9Whe4DeoDMNf0kAgalXylPV+lJwtMHGGI3VsAGOuaYGAmUANczK8utxAwaRgXXDiY4 c2xZvDERc9RWpxcwDjEFn4GKl2TEgDDLl7iEXcHQhGDMfB9yzDJRC/SQN6JRXfyQqMMMCO0p8n2m /pnVzFieAhyRaRckEgbZJf5VgcwGWCWHErwUNmfMQTRoGVrxGoA4sqOrbSYkQigwEQw2isondFDE IBRxGWlNQyqyUuSoHgF7FmATwwQFgKQmYehHUBTkdxDbOyYXLEExY6jkyrcjMJy2c3/EHb4UMS5O TuEVlRpXylk9JSjWDuHlJfn9AF2sw66zCqArBj1kTJYmAGPMwmrSZrG2vTMA9wje6gN+X0xqcbJU /fCZuNS7zfmAIek1LIarMa4iZf8AYIQupnDRo4lgqBkazAJW00QQVtufh++pOI1MOYAWuXS5hbnH iA1gCcXtg3OLVKnzBKg/XPxMCHdDD1KW+XByQMjT4r1GQbuk4YxRS89s5ioAsPmNK5MGZZUbMM3s HxLCyxxmMCX4y8vQZmxLLgVBS8w1LrDozew5eYF04YjgwdElEAy0uMNIoHCyjq3HRmI2rhqAC8zi 4qA0TBLSsHENjm9RcYazGyKlsM3rrqZasnBF1BL9UHljmShjcq9xHC4+deRLEvhhpcHMqi8gu5Up QViu5S6gVnmUCO6QTb26ixRTTKJ4EROAcQxYA6CCrg6GoUK/LEJoqcvSvH3gQ8ypr5iVy3FF1BMx OPzCVwx6IZnMSwLXAYOlyyu43HuhREHBxKEbvNQ6NTWvlA6it9yqe5lQgwl8GIb0OyJOO8y6HLua rWohO2aaPcZW2/M1+Iq9EIVuXTkVgeYdba53UGxWJFvzEa6uAUeMQgXshZUWVMLzKLmmdDfESrjq b4HSAHrUBZOAILtoltGajb5S0fzNXtiPJ6lhDTuWB0JVdGo2yy7Sh5ZfhUwxxKtncqUOdwvBmpeL wwdL6lY+9SIw6QxZiFEKgql4iFlktrCMqzM+Ce0l0yubP9mFbFczy4WhGvzLkJayir43qol/LMTM GZK4VBHDiKLh3b3quYpjYZloWzg8xB3yTPkv4qFOS5RVaYSo67miGjuLgx4qUd4+oWAKlHKrxKtb cY3m7jewR1K3bl6gm41uN8FHMTTbuUcPccW12RYZhqVobmLQG754iaeOpQmFy0WMMMtYiq1+4gZx WqlA+TTEFslylg0YHDSDNpdQJsNxlEU9S1xj3MwiKwM+5gGrPEHgxxHsx1N/8OZ//9k= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/header2.jpg /9j/4AAQSkZJRgABAgEASABIAAD/4QWuRXhpZgAATU0AKgAAAAgABwESAAMAAAABAAEAAAEaAAUA AAABAAAAYgEbAAUAAAABAAAAagEoAAMAAAABAAIAAAExAAIAAAAUAAAAcgEyAAIAAAAUAAAAhodp AAQAAAABAAAAnAAAAMgAAABIAAAAAQAAAEgAAAABQWRvYmUgUGhvdG9zaG9wIDcuMAAyMDAzOjA3 OjE1IDEwOjEzOjEzAAAAAAOgAQADAAAAAf//AACgAgAEAAAAAQAAAN+gAwAEAAAAAQAAAB0AAAAA AAAABgEDAAMAAAABAAYAAAEaAAUAAAABAAABFgEbAAUAAAABAAABHgEoAAMAAAABAAIAAAIBAAQA AAABAAABJgICAAQAAAABAAAEgAAAAAAAAABIAAAAAQAAAEgAAAAB/9j/4AAQSkZJRgABAgEASABI AAD/7QAMQWRvYmVfQ00AAv/uAA5BZG9iZQBkgAAAAAH/2wCEAAwICAgJCAwJCQwRCwoLERUPDAwP FRgTExUTExgRDAwMDAwMEQwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwBDQsLDQ4NEA4OEBQO Dg4UFA4ODg4UEQwMDAwMEREMDAwMDAwRDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDP/AABEI ABEAgAMBIgACEQEDEQH/3QAEAAj/xAE/AAABBQEBAQEBAQAAAAAAAAADAAECBAUGBwgJCgsBAAEF AQEBAQEBAAAAAAAAAAEAAgMEBQYHCAkKCxAAAQQBAwIEAgUHBggFAwwzAQACEQMEIRIxBUFRYRMi cYEyBhSRobFCIyQVUsFiMzRygtFDByWSU/Dh8WNzNRaisoMmRJNUZEXCo3Q2F9JV4mXys4TD03Xj 80YnlKSFtJXE1OT0pbXF1eX1VmZ2hpamtsbW5vY3R1dnd4eXp7fH1+f3EQACAgECBAQDBAUGBwcG BTUBAAIRAyExEgRBUWFxIhMFMoGRFKGxQiPBUtHwMyRi4XKCkkNTFWNzNPElBhaisoMHJjXC0kST VKMXZEVVNnRl4vKzhMPTdePzRpSkhbSVxNTk9KW1xdXl9VZmdoaWprbG1ub2JzdHV2d3h5ent8f/ 2gAMAwEAAhEDEQA/APP7Cwvd6YLa5OwOMuDfzQ9wDdztv8lQS3s/eH3hLez94feFs2O7bsKU63Na 4F3ChvZ+8PvCYuaWmHCY8QnRI4h5rZkcJ8m++xtmgMeEaIQx37pglVqngiSQPmjtyGtH0wSeACFd BFNfjx2CbKf0zILZJB1hXxU302XM1LdS3uPisptz3Gd7WjwDhK3umY/o47rXOEO4BPJQySoX/IqM 4V30bmZdjfYaG0VbbHQ94BiSf5KBTdZU4GSGnQktJifBXKnUWZlTbAGvLYAMbf7JVYOyPtNuMdrw 13saOBqY1VeJFcNdOI34loThAevi/STi6t2K9tjK7TYdswJA4bLXBVsnojcJgv6TlFlpG51JMt+B /dUPWrryCHxTt7uggu/6lBzerH6NljY4GwtAj+yiISv07bm9YyXYiOMHj0v6tRvV76rZ6lQRMgvb pP5VmZ2f67z6TNjS4lvcn4wukxbcDJaN72OMahxEINvR+jXlxa9tMautYZDP5Wyfcm5rMTCJ9sy9 MpcPF6D+66Q45gCMwa77/wCM89iVD6XIOhMrc6FiWO9ayIZXW5wceJ7rVo+q3UG4LnMqqzcZomu+ kw8j+qj9ExsK3CyMH1fs+Y4e6q72kQf5X0m7VFAY8WOsZEuHSRiP8Hjl+ky0I4qA123/AHvmf//Q 2Ul4iktJT7cl2XiKSIUdn24cqY5XhySet6PugVsfQavAEk09EPv7vot/rIzfof6+C+eklGVp2+r7 9kfzQ+KrP+gfmvCklJHYID7qOfkiVfSXgySUurLF+icP6P8AaKrZ/wDOr5/SUUdyp//Z/+0KRFBo b3Rvc2hvcCAzLjAAOEJJTQQlAAAAAAAQAAAAAAAAAAAAAAAAAAAAADhCSU0D7QAAAAAAEABIAAAA AQACAEgAAAABAAI4QklNBCYAAAAAAA4AAAAAAAAAAAAAP4AAADhCSU0EDQAAAAAABAAAAB44QklN BBkAAAAAAAQAAAAeOEJJTQPzAAAAAAAJAAAAAAAAAAABADhCSU0ECgAAAAAAAQAAOEJJTScQAAAA AAAKAAEAAAAAAAAAAjhCSU0D9QAAAAAASAAvZmYAAQBsZmYABgAAAAAAAQAvZmYAAQChmZoABgAA AAAAAQAyAAAAAQBaAAAABgAAAAAAAQA1AAAAAQAtAAAABgAAAAAAAThCSU0D+AAAAAAAcAAA//// /////////////////////////wPoAAAAAP////////////////////////////8D6AAAAAD///// ////////////////////////A+gAAAAA/////////////////////////////wPoAAA4QklNBAgA AAAAABAAAAABAAACQAAAAkAAAAAAOEJJTQQeAAAAAAAEAAAAADhCSU0EGgAAAAADQwAAAAYAAAAA AAAAAAAAAB0AAADfAAAABwBoAGUAYQBkAGUAcgAyAAAAAQAAAAAAAAAAAAAAAAAAAAAAAAABAAAA AAAAAAAAAADfAAAAHQAAAAAAAAAAAAAAAAAAAAABAAAAAAAAAAAAAAAAAAAAAAAAABAAAAABAAAA AAAAbnVsbAAAAAIAAAAGYm91bmRzT2JqYwAAAAEAAAAAAABSY3QxAAAABAAAAABUb3AgbG9uZwAA AAAAAAAATGVmdGxvbmcAAAAAAAAAAEJ0b21sb25nAAAAHQAAAABSZ2h0bG9uZwAAAN8AAAAGc2xp Y2VzVmxMcwAAAAFPYmpjAAAAAQAAAAAABXNsaWNlAAAAEgAAAAdzbGljZUlEbG9uZwAAAAAAAAAH Z3JvdXBJRGxvbmcAAAAAAAAABm9yaWdpbmVudW0AAAAMRVNsaWNlT3JpZ2luAAAADWF1dG9HZW5l cmF0ZWQAAAAAVHlwZWVudW0AAAAKRVNsaWNlVHlwZQAAAABJbWcgAAAABmJvdW5kc09iamMAAAAB AAAAAAAAUmN0MQAAAAQAAAAAVG9wIGxvbmcAAAAAAAAAAExlZnRsb25nAAAAAAAAAABCdG9tbG9u ZwAAAB0AAAAAUmdodGxvbmcAAADfAAAAA3VybFRFWFQAAAABAAAAAAAAbnVsbFRFWFQAAAABAAAA AAAATXNnZVRFWFQAAAABAAAAAAAGYWx0VGFnVEVYVAAAAAEAAAAAAA5jZWxsVGV4dElzSFRNTGJv b2wBAAAACGNlbGxUZXh0VEVYVAAAAAEAAAAAAAlob3J6QWxpZ25lbnVtAAAAD0VTbGljZUhvcnpB bGlnbgAAAAdkZWZhdWx0AAAACXZlcnRBbGlnbmVudW0AAAAPRVNsaWNlVmVydEFsaWduAAAAB2Rl ZmF1bHQAAAALYmdDb2xvclR5cGVlbnVtAAAAEUVTbGljZUJHQ29sb3JUeXBlAAAAAE5vbmUAAAAJ dG9wT3V0c2V0bG9uZwAAAAAAAAAKbGVmdE91dHNldGxvbmcAAAAAAAAADGJvdHRvbU91dHNldGxv bmcAAAAAAAAAC3JpZ2h0T3V0c2V0bG9uZwAAAAAAOEJJTQQRAAAAAAABAQA4QklNBBQAAAAAAAQA AAABOEJJTQQMAAAAAAScAAAAAQAAAIAAAAARAAABgAAAGYAAAASAABgAAf/Y/+AAEEpGSUYAAQIB AEgASAAA/+0ADEFkb2JlX0NNAAL/7gAOQWRvYmUAZIAAAAAB/9sAhAAMCAgICQgMCQkMEQsKCxEV DwwMDxUYExMVExMYEQwMDAwMDBEMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMAQ0LCw0ODRAO DhAUDg4OFBQODg4OFBEMDAwMDBERDAwMDAwMEQwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAz/ wAARCAARAIADASIAAhEBAxEB/90ABAAI/8QBPwAAAQUBAQEBAQEAAAAAAAAAAwABAgQFBgcICQoL AQABBQEBAQEBAQAAAAAAAAABAAIDBAUGBwgJCgsQAAEEAQMCBAIFBwYIBQMMMwEAAhEDBCESMQVB UWETInGBMgYUkaGxQiMkFVLBYjM0coLRQwclklPw4fFjczUWorKDJkSTVGRFwqN0NhfSVeJl8rOE w9N14/NGJ5SkhbSVxNTk9KW1xdXl9VZmdoaWprbG1ub2N0dXZ3eHl6e3x9fn9xEAAgIBAgQEAwQF BgcHBgU1AQACEQMhMRIEQVFhcSITBTKBkRShsUIjwVLR8DMkYuFygpJDUxVjczTxJQYWorKDByY1 wtJEk1SjF2RFVTZ0ZeLys4TD03Xj80aUpIW0lcTU5PSltcXV5fVWZnaGlqa2xtbm9ic3R1dnd4eX p7fH/9oADAMBAAIRAxEAPwDz+wsL3emC2uTsDjLg380PcA3c7b/JUEt7P3h94S3s/eH3hbNju27C lOtzWuBdwob2fvD7wmLmlphwmPEJ0SOIea2ZHCfJvvsbZoDHhGiEMd+6YJVap4IkkD5o7chrR9ME ngAhXQRTX48dgmyn9MyC2SQdYV8VN9NlzNS3Ut7j4rKbc9xne1o8A4St7pmP6OO61zhDuATyUMkq F/yKjOFd9G5mXY32GhtFW2x0PeAYkn+SgU3WVOBkhp0JLSYnwVyp1FmZU2wBry2ADG3+yVWDsj7T bjHa8Nd7GjgamNVXiRXDXTiN+JaE4QHr4v0k4urdivbYyu02HbMCQOGy1wVbJ6I3CYL+k5RZaRud STLfgf3VD1q68gh8U7e7oILv+pQc3qx+jZY2OBsLQI/soiEr9O25vWMl2IjjB49L+rUb1e+q2epU ETIL26T+VZmdn+u8+kzY0uJb3J+MLpMW3AyWje9jjGocRCDb0fo15cWvbTGrrWGQz+Vsn3JuazEw ifbMvTKXDxeg/uukOOYAjMGu+/8AjPPYlQ+lyDoTK3OhYljvWsiGV1ucHHie61aPqt1BuC5zKqs3 GaJrvpMPI/qo/RMbCtwsjB9X7PmOHuqu9pEH+V9Ju1RQGPFjrGRLh0kYj/B45fpMtCOKgNdt/wB7 5n//0NlJeIpLSU+3Jdl4ikiFHZ9uHKmOV4cknrej7oFbH0GrwBJNPRD7+76Lf6yM36H+vgvnpJRl advq+/ZH80Piqz/oH5rwpJSR2CA+6jn5IlX0l4MklLqyxfonD+j/AGiq2f8Azq+f0lFHcqf/2ThC SU0EIQAAAAAAVQAAAAEBAAAADwBBAGQAbwBiAGUAIABQAGgAbwB0AG8AcwBoAG8AcAAAABMAQQBk AG8AYgBlACAAUABoAG8AdABvAHMAaABvAHAAIAA3AC4AMAAAAAEAOEJJTQQGAAAAAAAHAAEBAQAB AQD/4RJIaHR0cDovL25zLmFkb2JlLmNvbS94YXAvMS4wLwA8P3hwYWNrZXQgYmVnaW49J++7vycg aWQ9J1c1TTBNcENlaGlIenJlU3pOVGN6a2M5ZCc/Pgo8P2Fkb2JlLXhhcC1maWx0ZXJzIGVzYz0i Q1IiPz4KPHg6eGFwbWV0YSB4bWxuczp4PSdhZG9iZTpuczptZXRhLycgeDp4YXB0az0nWE1QIHRv b2xraXQgMi44LjItMzMsIGZyYW1ld29yayAxLjUnPgo8cmRmOlJERiB4bWxuczpyZGY9J2h0dHA6 Ly93d3cudzMub3JnLzE5OTkvMDIvMjItcmRmLXN5bnRheC1ucyMnIHhtbG5zOmlYPSdodHRwOi8v bnMuYWRvYmUuY29tL2lYLzEuMC8nPgoKIDxyZGY6RGVzY3JpcHRpb24gYWJvdXQ9J3V1aWQ6N2Ji NTczZTctYjZhNC0xMWQ3LTlkZGItYWNiY2UyYTI2OTkxJwogIHhtbG5zOnhhcE1NPSdodHRwOi8v bnMuYWRvYmUuY29tL3hhcC8xLjAvbW0vJz4KICA8eGFwTU06RG9jdW1lbnRJRD5hZG9iZTpkb2Np ZDpwaG90b3Nob3A6N2JiNTczZTUtYjZhNC0xMWQ3LTlkZGItYWNiY2UyYTI2OTkxPC94YXBNTTpE b2N1bWVudElEPgogPC9yZGY6RGVzY3JpcHRpb24+Cgo8L3JkZjpSREY+CjwveDp4YXBtZXRhPgog ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg CiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAK ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKPD94cGFja2V0 IGVuZD0ndyc/Pv/uACFBZG9iZQBkgAAAAAEDABADAgMGAAAAAAAAAAAAAAAA/9sAhAAMCAgICQgM CQkMEQsKCxEVDwwMDxUYExMVExMYEQwMDAwMDBEMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwM AQ0LCw0ODRAODhAUDg4OFBQODg4OFBEMDAwMDBERDAwMDAwMEQwMDAwMDAwMDAwMDAwMDAwMDAwM DAwMDAwMDAz/wgARCAAdAN8DASIAAhEBAxEB/8QAtgAAAgIDAQAAAAAAAAAAAAAABAUAAwECBgcB AAIDAQAAAAAAAAAAAAAAAAIDAAEEBRAAAgICAwACAwEBAAAAAAAAAgMBBAAFERITEBQgIgYhFREA AQMDAgIHAwoHAAAAAAAAAQARAiEDBDESQdRRYSIyEzSUECCBoSNzk7PTJHS0xHGRscHRQ8MSAAED AgMGBAcBAAAAAAAAAAEAEQIhEjFBkhBRcSLSA0JSwuJhgdEyYoKyE//aAAwDAQECEQMRAAAA4KmT ta5JJJJJLzF1ulO9N+7hrzbm7I30NWLpMYGnnWEj4umKU9kq+X3ZoXdFsgrCA8k1MMR0vVvS7WcP GEQC+MJIvjCSLsMsacwtheGCJhhfLFfbHpoK/YpK+duOJYhLtZDtcaEXNJgjCL1qCX3SAfnnRrmY h//aAAgBAgABBQD5TA9fgp4lccYUQU8kED1KHtlA1ahTMl1ntGdoztGKOIH0HPWMazmZOOstHnuH JGExElhPbBNIpn//2gAIAQMAAQUA+S558+S6/sUR1JJEQiQ5+0SgmDBuIprxBS/iB7RnaM7RjCLv PfIlmFJcDJc8NwfTFkzgWYJjEtLkv//aAAgBAQABBQCwma9j8a8RMnI9WQeQM8iM8SJCSFdwQELb WpVxrHMQaXkBnZ5hi6ZVW/zTjmNjf1xRuK1gmeJIuWVcFMsKuHELjqwFyOu/KDkch/MAwSyAAs6i OdYLK1gVGyuTBI2qqjWIpmq3p3YMG/1irYYpF8U2AfpxHHKvqAv8xCSIxqmGVKwudZrgqj+TI/VU zMjPGAXEE7B9JmnXIyACQprAYs1yVNDnQxjRga5ScvtvHGWhI68LYMpAgbrKjML+YuIkkW/DUJqs tW9ZLC8dHnjo88dHnjo88dHnjo8NOi6JTochOiyU6TkU6HBVos1i9LGNDXdrIajpUCl9SA0X2LIa nwavSzhq13RqtN3qq1uedTpXXr+2mCt72Po/X2A/zc2a4M/5v//aAAgBAgIGPwDaDntY0BUpSLua Jwy5S7nAp7WlmiYxl3Cdw+1GfdjK57ogoRIYkiiz0+1Z6fas9PtVbtEj6VhLR3OlYS0dzpQBjK3e RIelC0HHyocktKevAxl9FRx+k+lcpl8oz6VEHtmf5W2TUZRuEvJKP8r/2gAIAQMCBj8A2kDenuZM 9GxRyKJCIdkM0CS4bAogxtLYlf6EhgakoRBxNy8WleLSvFpRtCriiywrxUnAZt6LYZVHUmID77oq sVzA6VyxJHwvQuuHGLL/2gAIAQEBBj8AuWJSjOVqRgZQIlEmJ2vbuR78Je8Ewotae0VTjVPJgOtH IjICUgpAS3F6Ibg5CBnB4yotsoRMiOKN7GMY8RHgvCyIkjgeCeXZkelGe+LAaIxtlyaJn0CZbvgp SbWJ+Ue+D7GK1VKqpZbe8/BCcWBlw6FGEgTReKQQ6MhMdOijvaUQdGQaLHRgjEQcNV0RdAJPDiFI 2pMToEYy3GHUmBMekFCMBufVlWJDagoRlQHRulWcdu1Nov8Ax990R7HJYdaaNSu1/IIMouKqO87S FKVsAkCikJ16k8404URlE7SNKraZEAIOX/ygX4KsQR1hNKIrRwNF4+LITjqw1QGVYIIHeZEGQiRo JUVicD2YEGRejOvOZfpbfPrzmX6W3z685l+lt8+vOZfpbfPrzmX6W3z685l+lt8+q5mXt/K2+fR2 5mV8cW3z6rmZXpbfPIbszLb8rab9chty8lurGhzq81kemt86g1+9I8N1mEf6ZM0N1699UPv12713 Sm21H79UvXDbbjaiC318lJ7t/f8ARxb5LyD3boj1W4k/bL5m/kRPVZjL9zBfOZORpxsQf9Wg2VlA vwxoH96hsycn448P7ZiH4i+30EeaVci6RV91iA/dFS8C7fIeviWoiP28kfH27Wro6HgXLsLr/wCu EZf9bauNfveHslWVmO9tp7v4jvL/2Q== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/button_my_account.jpg /9j/4AAQSkZJRgABAgEASABIAAD/4QiVRXhpZgAATU0AKgAAAAgABwESAAMAAAABAAEAAAEaAAUA AAABAAAAYgEbAAUAAAABAAAAagEoAAMAAAABAAIAAAExAAIAAAAUAAAAcgEyAAIAAAAUAAAAhodp AAQAAAABAAAAnAAAAMgAAABIAAAAAQAAAEgAAAABQWRvYmUgUGhvdG9zaG9wIDcuMAAyMDAzOjA3 OjE1IDEwOjEyOjQxAAAAAAOgAQADAAAAAf//AACgAgAEAAAAAQAAAFqgAwAEAAAAAQAAAB0AAAAA AAAABgEDAAMAAAABAAYAAAEaAAUAAAABAAABFgEbAAUAAAABAAABHgEoAAMAAAABAAIAAAIBAAQA AAABAAABJgICAAQAAAABAAAHZwAAAAAAAABIAAAAAQAAAEgAAAAB/9j/4AAQSkZJRgABAgEASABI AAD/7QAMQWRvYmVfQ00AAv/uAA5BZG9iZQBkgAAAAAH/2wCEAAwICAgJCAwJCQwRCwoLERUPDAwP FRgTExUTExgRDAwMDAwMEQwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwBDQsLDQ4NEA4OEBQO Dg4UFA4ODg4UEQwMDAwMEREMDAwMDAwRDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDP/AABEI AB0AWgMBIgACEQEDEQH/3QAEAAb/xAE/AAABBQEBAQEBAQAAAAAAAAADAAECBAUGBwgJCgsBAAEF AQEBAQEBAAAAAAAAAAEAAgMEBQYHCAkKCxAAAQQBAwIEAgUHBggFAwwzAQACEQMEIRIxBUFRYRMi cYEyBhSRobFCIyQVUsFiMzRygtFDByWSU/Dh8WNzNRaisoMmRJNUZEXCo3Q2F9JV4mXys4TD03Xj 80YnlKSFtJXE1OT0pbXF1eX1VmZ2hpamtsbW5vY3R1dnd4eXp7fH1+f3EQACAgECBAQDBAUGBwcG BTUBAAIRAyExEgRBUWFxIhMFMoGRFKGxQiPBUtHwMyRi4XKCkkNTFWNzNPElBhaisoMHJjXC0kST VKMXZEVVNnRl4vKzhMPTdePzRpSkhbSVxNTk9KW1xdXl9VZmdoaWprbG1ub2JzdHV2d3h5ent8f/ 2gAMAwEAAhEDEQA/AOUybsCnKsqttuLqnOY4NqaW7mktME3tdt9v7qr5NvTL3Bzbr2x29Fp/92UH qv8Aynmf8fZ/1TkR3RerMzMnBfivbk4TLLcqsgfo66m+pZa507PT2e6p+7Zdvr9D1PUrW0cp0Mpb CxYDZFiJHERxalQf0xv+HvP/AFhv/vSk49Kd/hb/APtlv/vSif8ANzrX/cf/ALRftL6df9E/7kfT /wDAv5//AINV+m9NzOqZleDg1+tk3bvTrkNna11j/fa5jPoMc76SUMtA8MwANTt6V0pGQIJseNMP s/S90/aL/h6Df/epOaOmER9ov/7Yb/71I1PRepX51/T66ZycT1DktLmtZUKdMh92Q5wx662OG31X W7P89ilT0Hql1mRWyprRiNa7Itssrrqa2wtGO77VbYzFc3J3tdiubb+tV/pKPUrUcjCUhKUgZDUW R18PlYvbhVftVjO6RSZNl7v+tMH/ALsFFdl9LJlr72+XpN/96EOjoXVciq24VNpqx7fs9r8myvGa LYc44+7Msoa69jWO9Spvvr/wia7oPV8cZzr8Z1Y6Wa25u5zQazadlGm79K2130X0b2fn/QUv3g3X uf8AQTwxoAGgG0zqXSmiC693/Wmj/wBHqFub0m3h97f+tNP/AKPQczoPV8E5bcrHLD091TcvaWvF ZvabMf1DU57dtjR9P6G/ZW/9JZWiYn1Z6xliz0K6iaqhkWB2RRWW1OrryW5D67rmPbR6F9TnW/QZ v9N/6SuytD7xWvuDz9C/i8fyQl/TDxdeP+st/wDelXv2ZV/p3f0b7b/Nj+Z8P53+kfyPof8ACLFu rNVjqnFpcxxaS0te0kGDtsqL2WN/dfW7Y9dJ/wDINO97J+9pvsP+9VxSu+I7eD//0OG6r/ynmf8A H2f9U5dQ/wCvxvs6o3JY84uVi5uNiOaJtP2iw3YQznOu2OrwWW21Uel/Ra7rK6/5xYvUqeiHqOUX 5eSH+s/cG41ZAO527a52c3/qVW9HoX/czK/9ha//AHvWpP2zw8enboz3Ghd7di3P+cP/AGH/APN/ fd6v231+f0XobP5j6e7+mfrPpel6O/8ASfzij0HrOL0jH6k99Rvy8zHGJTW4foDVY5pzRkenZRkN c6pjW0Ops+nvVb0ehf8AczK/9ha//e9N6PQp/pmV/wCwtf8A73pVi4ZC/SZXP+8q40d99dJO/Z9b +nX9ZzOo213N/a/TDhZ5a1p9O99bKX3YdJs/S4zfs9W2q/Jru99n6T/BrP6d1bpONgdX6S8ZDMTq bccV5LWsssa7Hf6svxvUx2bcmbPa3J/VfZX6mX/Pqh6PQv8AuZlf+wtf/vel6PQv+5mV/wCwtf8A 73oCOLoTXp/9df8AoCLj49Ohb1HVuk2dAt6JkDIxqvt326i6trMh201OxvQuDrMBu6tu13rt/nP9 BWtDO+t3TupZP1gbfVdj43W/s3pW1httlf2Qs9PfS6zHrd9pY3c7bk/oH/o/0/01g+j0L/uZlf8A sLX/AO96Xo9B/wC5mV/7C1/+96XDivc3en970/8AdcCrhfX7C7vUPru6zqfU+o4Nbqzn5GM70Lg1 9dmPRTkYd2Pm1/Rsbktuqe+j8z/T7667EJn1m6YzqfVMqrHsox8/pf7PxqAQ81v9HHxmB9j3tc+h n2Z36X+esZsf6ayPR6F/3Myv/YWv/wB703o9B/7mZX/sLX/73oCOHWj+iB/gemlXDx27SaC6f/5B rH9HoX/czK/9ha//AHvXR+n0v/uRf/yPH8wz+b/0n9K/nP8Agf8AwdTWL67diu4vPbtJ/9n/7Q1A UGhvdG9zaG9wIDMuMAA4QklNBCUAAAAAABAAAAAAAAAAAAAAAAAAAAAAOEJJTQPtAAAAAAAQAEgA AAABAAIASAAAAAEAAjhCSU0EJgAAAAAADgAAAAAAAAAAAAA/gAAAOEJJTQQNAAAAAAAEAAAAHjhC SU0EGQAAAAAABAAAAB44QklNA/MAAAAAAAkAAAAAAAAAAAEAOEJJTQQKAAAAAAABAAA4QklNJxAA AAAAAAoAAQAAAAAAAAACOEJJTQP1AAAAAABIAC9mZgABAGxmZgAGAAAAAAABAC9mZgABAKGZmgAG AAAAAAABADIAAAABAFoAAAAGAAAAAAABADUAAAABAC0AAAAGAAAAAAABOEJJTQP4AAAAAABwAAD/ ////////////////////////////A+gAAAAA/////////////////////////////wPoAAAAAP// //////////////////////////8D6AAAAAD/////////////////////////////A+gAADhCSU0E CAAAAAAAEAAAAAEAAAJAAAACQAAAAAA4QklNBB4AAAAAAAQAAAAAOEJJTQQaAAAAAANXAAAABgAA AAAAAAAAAAAAHQAAAFoAAAARAGIAdQB0AHQAbwBuAF8AbQB5AF8AYQBjAGMAbwB1AG4AdAAAAAEA AAAAAAAAAAAAAAAAAAAAAAAAAQAAAAAAAAAAAAAAWgAAAB0AAAAAAAAAAAAAAAAAAAAAAQAAAAAA AAAAAAAAAAAAAAAAAAAQAAAAAQAAAAAAAG51bGwAAAACAAAABmJvdW5kc09iamMAAAABAAAAAAAA UmN0MQAAAAQAAAAAVG9wIGxvbmcAAAAAAAAAAExlZnRsb25nAAAAAAAAAABCdG9tbG9uZwAAAB0A AAAAUmdodGxvbmcAAABaAAAABnNsaWNlc1ZsTHMAAAABT2JqYwAAAAEAAAAAAAVzbGljZQAAABIA AAAHc2xpY2VJRGxvbmcAAAAAAAAAB2dyb3VwSURsb25nAAAAAAAAAAZvcmlnaW5lbnVtAAAADEVT bGljZU9yaWdpbgAAAA1hdXRvR2VuZXJhdGVkAAAAAFR5cGVlbnVtAAAACkVTbGljZVR5cGUAAAAA SW1nIAAAAAZib3VuZHNPYmpjAAAAAQAAAAAAAFJjdDEAAAAEAAAAAFRvcCBsb25nAAAAAAAAAABM ZWZ0bG9uZwAAAAAAAAAAQnRvbWxvbmcAAAAdAAAAAFJnaHRsb25nAAAAWgAAAAN1cmxURVhUAAAA AQAAAAAAAG51bGxURVhUAAAAAQAAAAAAAE1zZ2VURVhUAAAAAQAAAAAABmFsdFRhZ1RFWFQAAAAB AAAAAAAOY2VsbFRleHRJc0hUTUxib29sAQAAAAhjZWxsVGV4dFRFWFQAAAABAAAAAAAJaG9yekFs aWduZW51bQAAAA9FU2xpY2VIb3J6QWxpZ24AAAAHZGVmYXVsdAAAAAl2ZXJ0QWxpZ25lbnVtAAAA D0VTbGljZVZlcnRBbGlnbgAAAAdkZWZhdWx0AAAAC2JnQ29sb3JUeXBlZW51bQAAABFFU2xpY2VC R0NvbG9yVHlwZQAAAABOb25lAAAACXRvcE91dHNldGxvbmcAAAAAAAAACmxlZnRPdXRzZXRsb25n AAAAAAAAAAxib3R0b21PdXRzZXRsb25nAAAAAAAAAAtyaWdodE91dHNldGxvbmcAAAAAADhCSU0E EQAAAAAAAQEAOEJJTQQUAAAAAAAEAAAAAThCSU0EDAAAAAAHgwAAAAEAAABaAAAAHQAAARAAAB7Q AAAHZwAYAAH/2P/gABBKRklGAAECAQBIAEgAAP/tAAxBZG9iZV9DTQAC/+4ADkFkb2JlAGSAAAAA Af/bAIQADAgICAkIDAkJDBELCgsRFQ8MDA8VGBMTFRMTGBEMDAwMDAwRDAwMDAwMDAwMDAwMDAwM DAwMDAwMDAwMDAwMDAENCwsNDg0QDg4QFA4ODhQUDg4ODhQRDAwMDAwREQwMDAwMDBEMDAwMDAwM DAwMDAwMDAwMDAwMDAwMDAwMDAwM/8AAEQgAHQBaAwEiAAIRAQMRAf/dAAQABv/EAT8AAAEFAQEB AQEBAAAAAAAAAAMAAQIEBQYHCAkKCwEAAQUBAQEBAQEAAAAAAAAAAQACAwQFBgcICQoLEAABBAED AgQCBQcGCAUDDDMBAAIRAwQhEjEFQVFhEyJxgTIGFJGhsUIjJBVSwWIzNHKC0UMHJZJT8OHxY3M1 FqKygyZEk1RkRcKjdDYX0lXiZfKzhMPTdePzRieUpIW0lcTU5PSltcXV5fVWZnaGlqa2xtbm9jdH V2d3h5ent8fX5/cRAAICAQIEBAMEBQYHBwYFNQEAAhEDITESBEFRYXEiEwUygZEUobFCI8FS0fAz JGLhcoKSQ1MVY3M08SUGFqKygwcmNcLSRJNUoxdkRVU2dGXi8rOEw9N14/NGlKSFtJXE1OT0pbXF 1eX1VmZ2hpamtsbW5vYnN0dXZ3eHl6e3x//aAAwDAQACEQMRAD8A5TJuwKcqyq224uqc5jg2ppbu aS0wTe1232/uqvk29MvcHNuvbHb0Wn/3ZQeq/wDKeZ/x9n/VORHdF6szMycF+K9uThMstyqyB+jr qb6llrnTs9PZ7qn7tl2+v0PU9StbRynQylsLFgNkWIkcRHFqVB/TG/4e8/8AWG/+9KTj0p3+Fv8A +2W/+9KJ/wA3Otf9x/8AtF+0vp1/0T/uR9P/AMC/n/8Ag1X6b03M6pmV4ODX62Tdu9OuQ2drXWP9 9rmM+gxzvpJQy0DwzAA1O3pXSkZAgmx40w+z9L3T9ov+HoN/96k5o6YRH2i//thv/vUjU9F6lfnX 9PrpnJxPUOS0ua1lQp0yH3ZDnDHrrY4bfVdbs/z2KVPQeqXWZFbKmtGI1rsi2yyuuprbC0Y7vtVt jMVzcne12K5tv61X+ko9StRyMJSEpSBkNRZHXw+Vi9uFV+1WM7pFJk2Xu/60wf8AuwUV2X0smWvv b5ek3/3oQ6OhdVyKrbhU2mrHt+z2vybK8Zothzjj7syyhrr2NY71Km++v/CJrug9XxxnOvxnVjpZ rbm7nNBrNp2Uabv0rbXfRfRvZ+f9BS/eDde5/wBBPDGgAaAbTOpdKaILr3f9aaP/AEeoW5vSbeH3 t/600/8Ao9BzOg9XwTltyscsPT3VNy9pa8Vm9psx/UNTnt22NH0/ob9lb/0llaJifVnrGWLPQrqJ qqGRYHZFFZbU6uvJbkPruuY9tHoX1Odb9Bm/03/pK7K0PvFa+4PP0L+Lx/JCX9MPF14/6y3/AN6V e/ZlX+nd/Rvtv82P5nw/nf6R/I+h/wAIsW6s1WOqcWlzHFpLS17SQYO2yovZY3919btj10n/AMg0 73sn72m+w/71XFK74jt4P//Q4bqv/KeZ/wAfZ/1Tl1D/AK/G+zqjcljzi5WLm42I5om0/aLDdhDO c67Y6vBZbbVR6X9Frusrr/nFi9Sp6Ieo5Rfl5If6z9wbjVkA7nbtrnZzf+pVb0ehf9zMr/2Fr/8A e9ak/bPDx6dujPcaF3t2Lc/5w/8AYf8A83993q/bfX5/Rehs/mPp7v6Z+s+l6Xo7/wBJ/OKPQes4 vSMfqT31G/LzMcYlNbh+gNVjmnNGR6dlGQ1zqmNbQ6mz6e9VvR6F/wBzMr/2Fr/9703o9Cn+mZX/ ALC1/wDvelWLhkL9Jlc/7yrjR3310k79n1v6df1nM6jbXc39r9MOFnlrWn0731spfdh0mz9LjN+z 1bar8mu732fpP8Gs/p3Vuk42B1fpLxkMxOptxxXktayyxrsd/qy/G9THZtyZs9rcn9V9lfqZf8+q Ho9C/wC5mV/7C1/+96Xo9C/7mZX/ALC1/wDvegI4uhNen/11/wCgIuPj06FvUdW6TZ0C3omQMjGq +3fbqLq2syHbTU7G9C4OswG7q27Xeu3+c/0Fa0M763dO6lk/WBt9V2Pjdb+zelbWG22V/ZCz099L rMet32ljdztuT+gf+j/T/TWD6PQv+5mV/wCwtf8A73pej0H/ALmZX/sLX/73pcOK9zd6f3vT/wB1 wKuF9fsLu9Q+u7rOp9T6jg1urOfkYzvQuDX12Y9FORh3Y+bX9GxuS26p76PzP9PvrrsQmfWbpjOp 9UyqseyjHz+l/s/GoBDzW/0cfGYH2Pe1z6GfZnfpf56xmx/prI9HoX/czK/9ha//AHvTej0H/uZl f+wtf/vegI4daP6IH+B6aVcPHbtJoLp//kGsf0ehf9zMr/2Fr/8Ae9dH6fS/+5F//I8fzDP5v/Sf 0r+c/wCB/wDB1NYvrt2K7i89u0n/2QA4QklNBCEAAAAAAFUAAAABAQAAAA8AQQBkAG8AYgBlACAA UABoAG8AdABvAHMAaABvAHAAAAATAEEAZABvAGIAZQAgAFAAaABvAHQAbwBzAGgAbwBwACAANwAu ADAAAAABADhCSU0EBgAAAAAABwABAQEAAQEA/+ESSGh0dHA6Ly9ucy5hZG9iZS5jb20veGFwLzEu MC8APD94cGFja2V0IGJlZ2luPSfvu78nIGlkPSdXNU0wTXBDZWhpSHpyZVN6TlRjemtjOWQnPz4K PD9hZG9iZS14YXAtZmlsdGVycyBlc2M9IkNSIj8+Cjx4OnhhcG1ldGEgeG1sbnM6eD0nYWRvYmU6 bnM6bWV0YS8nIHg6eGFwdGs9J1hNUCB0b29sa2l0IDIuOC4yLTMzLCBmcmFtZXdvcmsgMS41Jz4K PHJkZjpSREYgeG1sbnM6cmRmPSdodHRwOi8vd3d3LnczLm9yZy8xOTk5LzAyLzIyLXJkZi1zeW50 YXgtbnMjJyB4bWxuczppWD0naHR0cDovL25zLmFkb2JlLmNvbS9pWC8xLjAvJz4KCiA8cmRmOkRl c2NyaXB0aW9uIGFib3V0PSd1dWlkOjdiYjU3M2UxLWI2YTQtMTFkNy05ZGRiLWFjYmNlMmEyNjk5 MScKICB4bWxuczp4YXBNTT0naHR0cDovL25zLmFkb2JlLmNvbS94YXAvMS4wL21tLyc+CiAgPHhh cE1NOkRvY3VtZW50SUQ+YWRvYmU6ZG9jaWQ6cGhvdG9zaG9wOjRiOGM1OWUyLWI2YTQtMTFkNy05 ZGRiLWFjYmNlMmEyNjk5MTwveGFwTU06RG9jdW1lbnRJRD4KIDwvcmRmOkRlc2NyaXB0aW9uPgoK PC9yZGY6UkRGPgo8L3g6eGFwbWV0YT4KICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAK ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg IAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAog ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgCjw/eHBhY2tldCBlbmQ9J3cnPz7/7gAhQWRvYmUAZIAAAAABAwAQAwID BgAAAAAAAAAAAAAAAP/bAIQADAgICAkIDAkJDBELCgsRFQ8MDA8VGBMTFRMTGBEMDAwMDAwRDAwM DAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAENCwsNDg0QDg4QFA4ODhQUDg4ODhQRDAwMDAwREQwM DAwMDBEMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwM/8IAEQgAHQBaAwEiAAIRAQMRAf/EALwA AAIDAQEAAAAAAAAAAAAAAAMEAAUGAgEBAAMBAQEAAAAAAAAAAAAAAAABAgMEBRAAAQQCAgICAwAA AAAAAAAABQABAgMRBBITFAY1FhAVJhEAAgECAggCAwsMAwAAAAAAAgMEAAESExEyIzMUNNQFIpQh gyRSskNTY3OTo8PEFRAxQVFhcUJikkRUhTUGFhIAAQIEAwQLAQAAAAAAAAAAAQARITFBAlESImGR MnJxobHBQoKywtLiEzP/2gAMAwEBAhEDEQAAAMqsEntdMhFx8em6zzhR+atrgJFYXqXSUUWopVue HOVvAv69CJPWFDAvRU8Qhp6fR7V//9oACAECAAEFAHtdQtw0nhKXkPnyMLusU+t1iri0alxqzxpx ls//2gAIAQMAAQUAbLRlJ5N1wxxjjkuUs5jjMcZjjMM5guS//9oACAEBAAEFANm7Qp2ti0ZfOMxk VJxUl44vk9Ix21pCaXlti3eBIVFrd0TanmMdfrKkV+TkFLQ3PrhlDRu4U3KQpK/epAlL7KARXYqu Al9dt0CX0X1PWTG2rq3qsRX5Ofvz32/Yf48AZ1BGvZ7eOvMjiwnW0KCwiwBve3DiWyQ93lYTh7MM gT/BKkI5HpArpBLpBZ6QK6QK6QK6QS6QK6QK6QK6xa//2gAIAQICBj8ABuukHDgI5bwAImWlC664 G4RDkV2cKb9PQs36Dp0LihOQ+Ktzwworg+k3PfzKBLaer+X0Uy7w5tPuyIsfCB5NLKssCv/aAAgB AwIGPwAjMRmiUQbnG1k3egAWAU+xPmMtiDvLAoznGFyrShVdxVZYFV3XL//aAAgBAQEGPwBimtdc lEQHYVDccQ3uN9F7vEsPh9zVis546P0ZI3+81v339QPU1vX/AEI9VWniH/uyB6qtHEP+gHqq03Y8 vVBb7wVaRN4/syh6itFyeXqht9vXoJ4+qG/29ehz7epHqa35ctxu7tuv1b3mP5NT5Spnz7PfFUmC cUxkwgNspd7W2a1DmMaRacGXg8SjxYHY15GZmLrl/wCy/EtdfKf5Gv8AVb/5OlwYK86S7Flr02HT hEml42kAagFrFT+3rTpkxMy8kbkIgqyfRIN0gitHWsCthzSbg/rCpCwUI2iCJSGsYtahFlxsguKc wIpDJxgUUhb7UvaIzF011lClUdvDtOSxcYbN0EV4+KYxAk8BAsxQ+NfwlTifGJdu13WM3FcbXXdt 8CPRi2otLVNGMMG01KljKj3C/byUMvDcTsu7xuyPmXURjhYNtfUx4FntGLpl0LVe6lWkMsUhC7io lrkjINbnAYoyHqIm6gY8s9oti6JRXG5AVxvcbidr3tfRfCxVzBg+5NZYDr/R1M+fb74q7qEkDvFl RZsaIQ20tvxDLuhWnETsBLgg1qkZXKrcxa95X/n8bs3jc/8APssjBuNfFzntOVlZOPabyu5Garvl zI9oiVlbYXUwhvNtIy2IkCRKARQSWa+OpncmrcP4v2y8KfcRHZvNYJN0NN2bWN7OrCp8lbvGzafB 13ftJ2kBE7mMey5IiDGCUc83ScbMjhhk4meEZPsvgXmS9/TeySLSIyuO45DViEgsN1FGyHWJkAcS xwlnjvPiF1/2AXqdHjd74XKauwtYvhLhl5iSZHWXEgGIsMnYHs9vr13PuMFZLvPkRiyHWE1sjoTI hujzV6rBki5Rmj+D4/MWtld0lKjsTHn9r/D4yLXsd1nkx4wWNhmJGgOGLa75gePL/J/o6lXOXJse ceKwxl3ta+IsWEinD72ucleVX19c5K8qvr65yV5VfX1zkryq+vrnJXlV9fXOSvKr6+ucleVX19c5 K8qvr65yV5VfX1zkryq+vrmH/wDD6NwG7+M5refI/X1//9k= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/button_ealerts.jpg /9j/4AAQSkZJRgABAgEASABIAAD/4QfkRXhpZgAATU0AKgAAAAgABwESAAMAAAABAAEAAAEaAAUA AAABAAAAYgEbAAUAAAABAAAAagEoAAMAAAABAAIAAAExAAIAAAAUAAAAcgEyAAIAAAAUAAAAhodp AAQAAAABAAAAnAAAAMgAAABIAAAAAQAAAEgAAAABQWRvYmUgUGhvdG9zaG9wIDcuMAAyMDAzOjA3 OjE1IDEwOjEyOjU2AAAAAAOgAQADAAAAAf//AACgAgAEAAAAAQAAAE+gAwAEAAAAAQAAAB0AAAAA AAAABgEDAAMAAAABAAYAAAEaAAUAAAABAAABFgEbAAUAAAABAAABHgEoAAMAAAABAAIAAAIBAAQA AAABAAABJgICAAQAAAABAAAGtgAAAAAAAABIAAAAAQAAAEgAAAAB/9j/4AAQSkZJRgABAgEASABI AAD/7QAMQWRvYmVfQ00AAv/uAA5BZG9iZQBkgAAAAAH/2wCEAAwICAgJCAwJCQwRCwoLERUPDAwP FRgTExUTExgRDAwMDAwMEQwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwBDQsLDQ4NEA4OEBQO Dg4UFA4ODg4UEQwMDAwMEREMDAwMDAwRDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDP/AABEI AB0ATwMBIgACEQEDEQH/3QAEAAX/xAE/AAABBQEBAQEBAQAAAAAAAAADAAECBAUGBwgJCgsBAAEF AQEBAQEBAAAAAAAAAAEAAgMEBQYHCAkKCxAAAQQBAwIEAgUHBggFAwwzAQACEQMEIRIxBUFRYRMi cYEyBhSRobFCIyQVUsFiMzRygtFDByWSU/Dh8WNzNRaisoMmRJNUZEXCo3Q2F9JV4mXys4TD03Xj 80YnlKSFtJXE1OT0pbXF1eX1VmZ2hpamtsbW5vY3R1dnd4eXp7fH1+f3EQACAgECBAQDBAUGBwcG BTUBAAIRAyExEgRBUWFxIhMFMoGRFKGxQiPBUtHwMyRi4XKCkkNTFWNzNPElBhaisoMHJjXC0kST VKMXZEVVNnRl4vKzhMPTdePzRpSkhbSVxNTk9KW1xdXl9VZmdoaWprbG1ub2JzdHV2d3h5ent8f/ 2gAMAwEAAhEDEQA/AOJqpZb6r7XOrroZve5rQ4mXMqADC6tv+E/fUC3ppBH2i/X/AIBv/vUi1v3Y +aP+Aaf/AAbHVXGxrsrJqxaG778h7aqmyBL3nZW3c4hrdzv3ltc1ihOZM9a8abUiJE66AsvQ6Yec i/8A7Yb/AO9SdtPS2kkZF5n/AIBv/vUidR6Vl9Ms9HL9Jtu5zXMruqtc1zCG2NuZjW3Opc2fo27P +g9S6R0XqfWsl2J0yn7Rexhtczc1nsBawum51bfpWN/OUUY4445RiQMctZa2P8aSwQiDxXt1Y7em bdvr3x/xDf8A3qUfT6Z/3Iv/AO2Gf+9SWP07NyMLKzqa92Ng+n9pslo2+qTVT7HOD7N7xt/RNf8A y0f9hdR/Z1fU3NqrxLxY6l9l9NbrBUSy70qLLWX2urePo117/wDtxiYOXwRNgUQa+br83Cu07/kg rr6XW7cb7z5eg0f+7KtNy+lgQLL/APtpv/vQnt+rHW68QZbqGmo44zdrbanWfZnRGV9lrsdleh7v fZ6Xs/P2emlf9WOs4+NTkvrqdVknbjelkUXOtdubQW4tWPdbbkuba9rXeg1+z/CKwOY2AyDt+gti IxHCDpd9N0V1vSrWkG28T39Jv/vQh04XTrj6deRduDXvM0tAhjXW2f8Aan6Wxjtv8tLqHSc/ptnp ZjGtducwlj2WtD2GLaXWY77K231S31aHO9ZnqV72fpK1Hp38+7/iMj/zzahOZyRsyEq9UdBVqlEE E7+kjo//0OJx5+y5s8+gJ/7ex1HpGXXg9Xws62XVYuRVc9rQCS2t7bHBocW+7a32+5aFFPRvs+Z+ t5R/QjcTjMBA9Wj6P677n7/TVP0ehf8AczK/9ha//e9bGThuesiCTdghsmd7gjQdJdm/17rmPmdT PUcAteXW3W+nfg4tYaLTLW27DlftBzWl36XLbvY/9Iz9JYidH+tNfSOnZXo0Nu6jm5dN9jbGBuMK 8cnJx/RZiWYz6725rt/pf0b0Wens/wAGs30ehf8AczK/9ha//e9IU9C7ZmV/7C1/+96irFwgE+nT WvH/AL5bca615F27frD0G3/nHQPtdWN122i6qz06rLGOrsdlZPq1faKGbXXv20bbf5v+c96hk9f6 XZ9WsPpFb7Rbgtymh9uHj2iwX2Osp2W3Xvv6e7Zt9V+Nvex/0PU9CtY3o9A/7mZX/sLX/wC96Xo9 A/7mZX/sLX/73pcOOh6juP8AG4OH939xFx8d+x7eT0Nn1xwL8Srpz6rKsY9Kp6fdl1V1jKrsqlz/ AEbN7XZHT8lwrryMW2+n1GfQ9Cz+fysnruNZ0joOHWLm39Ife+57C2sn1bWZFZxbx6zq7G7P511P sf8AmWKn6PQf+5mV/wCwtf8A73pej0H/ALmZX/sLX/73pRjiFUevj81S/wC5Vcel79i2vrF1Xp/U zjPorc7MY2w52c6qvHOQ99jrKy/ExX2UNdUw7XZHqetfv/SfzaodO/pD/wDiMj/zzajej0L/ALmZ X/sLX/73o+DT0T1nbMvJJ9G+ZxawI9K3f/2ud+YnDhECI2RRrRJI4SBex6F//9n/7QyIUGhvdG9z aG9wIDMuMAA4QklNBCUAAAAAABAAAAAAAAAAAAAAAAAAAAAAOEJJTQPtAAAAAAAQAEgAAAABAAIA SAAAAAEAAjhCSU0EJgAAAAAADgAAAAAAAAAAAAA/gAAAOEJJTQQNAAAAAAAEAAAAHjhCSU0EGQAA AAAABAAAAB44QklNA/MAAAAAAAkAAAAAAAAAAAEAOEJJTQQKAAAAAAABAAA4QklNJxAAAAAAAAoA AQAAAAAAAAACOEJJTQP1AAAAAABIAC9mZgABAGxmZgAGAAAAAAABAC9mZgABAKGZmgAGAAAAAAAB ADIAAAABAFoAAAAGAAAAAAABADUAAAABAC0AAAAGAAAAAAABOEJJTQP4AAAAAABwAAD///////// ////////////////////A+gAAAAA/////////////////////////////wPoAAAAAP////////// //////////////////8D6AAAAAD/////////////////////////////A+gAADhCSU0ECAAAAAAA EAAAAAEAAAJAAAACQAAAAAA4QklNBB4AAAAAAAQAAAAAOEJJTQQaAAAAAANRAAAABgAAAAAAAAAA AAAAHQAAAE8AAAAOAGIAdQB0AHQAbwBuAF8AZQBhAGwAZQByAHQAcwAAAAEAAAAAAAAAAAAAAAAA AAAAAAAAAQAAAAAAAAAAAAAATwAAAB0AAAAAAAAAAAAAAAAAAAAAAQAAAAAAAAAAAAAAAAAAAAAA AAAQAAAAAQAAAAAAAG51bGwAAAACAAAABmJvdW5kc09iamMAAAABAAAAAAAAUmN0MQAAAAQAAAAA VG9wIGxvbmcAAAAAAAAAAExlZnRsb25nAAAAAAAAAABCdG9tbG9uZwAAAB0AAAAAUmdodGxvbmcA AABPAAAABnNsaWNlc1ZsTHMAAAABT2JqYwAAAAEAAAAAAAVzbGljZQAAABIAAAAHc2xpY2VJRGxv bmcAAAAAAAAAB2dyb3VwSURsb25nAAAAAAAAAAZvcmlnaW5lbnVtAAAADEVTbGljZU9yaWdpbgAA AA1hdXRvR2VuZXJhdGVkAAAAAFR5cGVlbnVtAAAACkVTbGljZVR5cGUAAAAASW1nIAAAAAZib3Vu ZHNPYmpjAAAAAQAAAAAAAFJjdDEAAAAEAAAAAFRvcCBsb25nAAAAAAAAAABMZWZ0bG9uZwAAAAAA AAAAQnRvbWxvbmcAAAAdAAAAAFJnaHRsb25nAAAATwAAAAN1cmxURVhUAAAAAQAAAAAAAG51bGxU RVhUAAAAAQAAAAAAAE1zZ2VURVhUAAAAAQAAAAAABmFsdFRhZ1RFWFQAAAABAAAAAAAOY2VsbFRl eHRJc0hUTUxib29sAQAAAAhjZWxsVGV4dFRFWFQAAAABAAAAAAAJaG9yekFsaWduZW51bQAAAA9F U2xpY2VIb3J6QWxpZ24AAAAHZGVmYXVsdAAAAAl2ZXJ0QWxpZ25lbnVtAAAAD0VTbGljZVZlcnRB bGlnbgAAAAdkZWZhdWx0AAAAC2JnQ29sb3JUeXBlZW51bQAAABFFU2xpY2VCR0NvbG9yVHlwZQAA AABOb25lAAAACXRvcE91dHNldGxvbmcAAAAAAAAACmxlZnRPdXRzZXRsb25nAAAAAAAAAAxib3R0 b21PdXRzZXRsb25nAAAAAAAAAAtyaWdodE91dHNldGxvbmcAAAAAADhCSU0EEQAAAAAAAQEAOEJJ TQQUAAAAAAAEAAAAAThCSU0EDAAAAAAG0gAAAAEAAABPAAAAHQAAAPAAABswAAAGtgAYAAH/2P/g ABBKRklGAAECAQBIAEgAAP/tAAxBZG9iZV9DTQAC/+4ADkFkb2JlAGSAAAAAAf/bAIQADAgICAkI DAkJDBELCgsRFQ8MDA8VGBMTFRMTGBEMDAwMDAwRDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwM DAENCwsNDg0QDg4QFA4ODhQUDg4ODhQRDAwMDAwREQwMDAwMDBEMDAwMDAwMDAwMDAwMDAwMDAwM DAwMDAwMDAwM/8AAEQgAHQBPAwEiAAIRAQMRAf/dAAQABf/EAT8AAAEFAQEBAQEBAAAAAAAAAAMA AQIEBQYHCAkKCwEAAQUBAQEBAQEAAAAAAAAAAQACAwQFBgcICQoLEAABBAEDAgQCBQcGCAUDDDMB AAIRAwQhEjEFQVFhEyJxgTIGFJGhsUIjJBVSwWIzNHKC0UMHJZJT8OHxY3M1FqKygyZEk1RkRcKj dDYX0lXiZfKzhMPTdePzRieUpIW0lcTU5PSltcXV5fVWZnaGlqa2xtbm9jdHV2d3h5ent8fX5/cR AAICAQIEBAMEBQYHBwYFNQEAAhEDITESBEFRYXEiEwUygZEUobFCI8FS0fAzJGLhcoKSQ1MVY3M0 8SUGFqKygwcmNcLSRJNUoxdkRVU2dGXi8rOEw9N14/NGlKSFtJXE1OT0pbXF1eX1VmZ2hpamtsbW 5vYnN0dXZ3eHl6e3x//aAAwDAQACEQMRAD8A4mqllvqvtc6uuhm97mtDiZcyoAMLq2/4T99QLemk EfaL9f8AgG/+9SLW/dj5o/4Bp/8ABsdVcbGuysmrFobvvyHtqqbIEvedlbdziGt3O/eW1zWKE5kz 1rxptSIkTroCy9Dph5yL/wDthv8A71J209LaSRkXmf8AgG/+9SJ1HpWX0yz0cv0m27nNcyu6q1zX MIbY25mNbc6lzZ+jbs/6D1LpHRep9ayXYnTKftF7GG1zNzWewFrC6bnVt+lY385RRjjjjlGJAxy1 lrY/xpLBCIPFe3Vjt6Zt2+vfH/EN/wDepR9Ppn/ci/8A7YZ/71JY/Ts3IwsrOpr3Y2D6f2myWjb6 pNVPsc4Ps3vG39E1/wDLR/2F1H9nV9Tc2qvEvFjqX2X01usFRLLvSostZfa6t4+jXXv/AO3GJg5f BE2BRBr5uvzcK7Tv+SCuvpdbtxvvPl6DR/7sq03L6WBAsv8A+2m/+9Ce36sdbrxBluoaajjjN2tt qdZ9mdEZX2Wux2V6Hu99npez8/Z6aV/1Y6zj41OS+up1WSduN6WRRc6125tBbi1Y91tuS5tr2td6 DX7P8IrA5jYDIO36C2IjEcIOl303RXW9KtaQbbxPf0m/+9CHThdOuPp15F24Ne8zS0CGNdbZ/wBq fpbGO2/y0uodJz+m2elmMa125zCWPZa0PYYtpdZjvsrbfVLfVoc71mepXvZ+krUenfz7v+IyP/PN qE5nJGzISr1R0FWqUQQTv6SOj//Q4nHn7Lmzz6An/t7HUekZdeD1fCzrZdVi5FVz2tAJLa3tscGh xb7trfb7loUU9G+z5n63lH9CNxOMwED1aPo/rvufv9NU/R6F/wBzMr/2Fr/971sZOG56yIJN2CGy Z3uCNB0l2b/XuuY+Z1M9RwC15dbdb6d+Di1hotMtbbsOV+0HNaXfpctu9j/0jP0liJ0f6019I6dl ejQ27qObl032NsYG4wrxycnH9FmJZjPrvbmu3+l/RvRZ6ez/AAazfR6F/wBzMr/2Fr/970hT0Ltm ZX/sLX/73qKsXCAT6dNa8f8AvltxrrXkXbt+sPQbf+cdA+11Y3XbaLqrPTqssY6ux2Vk+rV9ooZt de/bRtt/m/5z3qGT1/pdn1aw+kVvtFuC3KaH24ePaLBfY6ynZbde+/p7tm31X4297H/Q9T0K1jej 0D/uZlf+wtf/AL3pej0D/uZlf+wtf/velw46HqO4/wAbg4f3f3EXHx37Ht5PQ2fXHAvxKunPqsqx j0qnp92XVXWMquyqXP8ARs3tdkdPyXCuvIxbb6fUZ9D0LP5/Kyeu41nSOg4dYubf0h977nsLayfV tZkVnFvHrOrsbs/nXU+x/wCZYqfo9B/7mZX/ALC1/wDvel6PQf8AuZlf+wtf/velGOIVR6+PzVL/ ALlVx6Xv2La+sXVen9TOM+itzsxjbDnZzqq8c5D32OsrL8TFfZQ11TDtdkep61+/9J/Nqh07+kP/ AOIyP/PNqN6PQv8AuZlf+wtf/vej4NPRPWdsy8kn0b5nFrAj0rd//a535icOEQIjZFGtEkjhIF7H oX//2ThCSU0EIQAAAAAAVQAAAAEBAAAADwBBAGQAbwBiAGUAIABQAGgAbwB0AG8AcwBoAG8AcAAA ABMAQQBkAG8AYgBlACAAUABoAG8AdABvAHMAaABvAHAAIAA3AC4AMAAAAAEAOEJJTQQGAAAAAAAH AAEBAQABAQD/4RJIaHR0cDovL25zLmFkb2JlLmNvbS94YXAvMS4wLwA8P3hwYWNrZXQgYmVnaW49 J++7vycgaWQ9J1c1TTBNcENlaGlIenJlU3pOVGN6a2M5ZCc/Pgo8P2Fkb2JlLXhhcC1maWx0ZXJz IGVzYz0iQ1IiPz4KPHg6eGFwbWV0YSB4bWxuczp4PSdhZG9iZTpuczptZXRhLycgeDp4YXB0az0n WE1QIHRvb2xraXQgMi44LjItMzMsIGZyYW1ld29yayAxLjUnPgo8cmRmOlJERiB4bWxuczpyZGY9 J2h0dHA6Ly93d3cudzMub3JnLzE5OTkvMDIvMjItcmRmLXN5bnRheC1ucyMnIHhtbG5zOmlYPSdo dHRwOi8vbnMuYWRvYmUuY29tL2lYLzEuMC8nPgoKIDxyZGY6RGVzY3JpcHRpb24gYWJvdXQ9J3V1 aWQ6N2JiNTczZTMtYjZhNC0xMWQ3LTlkZGItYWNiY2UyYTI2OTkxJwogIHhtbG5zOnhhcE1NPSdo dHRwOi8vbnMuYWRvYmUuY29tL3hhcC8xLjAvbW0vJz4KICA8eGFwTU06RG9jdW1lbnRJRD5hZG9i ZTpkb2NpZDpwaG90b3Nob3A6NGI4YzU5ZTEtYjZhNC0xMWQ3LTlkZGItYWNiY2UyYTI2OTkxPC94 YXBNTTpEb2N1bWVudElEPgogPC9yZGY6RGVzY3JpcHRpb24+Cgo8L3JkZjpSREY+CjwveDp4YXBt ZXRhPgogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg IAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAog ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg CiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKPD94 cGFja2V0IGVuZD0ndyc/Pv/uACFBZG9iZQBkgAAAAAEDABADAgMGAAAAAAAAAAAAAAAA/9sAhAAM CAgICQgMCQkMEQsKCxEVDwwMDxUYExMVExMYEQwMDAwMDBEMDAwMDAwMDAwMDAwMDAwMDAwMDAwM DAwMDAwMAQ0LCw0ODRAODhAUDg4OFBQODg4OFBEMDAwMDBERDAwMDAwMEQwMDAwMDAwMDAwMDAwM DAwMDAwMDAwMDAwMDAz/wgARCAAdAE8DASIAAhEBAxEB/8QAqwAAAgMBAQAAAAAAAAAAAAAAAgMA BAUBBgEAAwEBAQAAAAAAAAAAAAAAAAECAwQFEAABBAIDAAMBAAAAAAAAAAAFAQIDBAATERIGMxQV IREAAgIABAMFBAcJAQAAAAAAAgMBBAAREhMi1AUyIxQ0lCFCM5NiQ2NzsyREMUFhUpKio8QVBhIA AQMDAwIHAQAAAAAAAAAAAQARAiExQVESImEycbFCUpLSA8L/2gAMAwEBAhEDEQAAAPEg2r7XUXWF lAjHxSLRc6JUuCgx0Kaq+zM7lO2GNBehyqcC1nvsU//aAAgBAgABBQC1Ex72NjbGleBqpYx71kbJ 154h69Y+GtiTE6oz/9oACAEDAAEFAHKjlRjUX+Y1EajmoqK/nOW8ctzluKqdf//aAAgBAQABBQCK FkuK0aqaBi4yEW1eozrrGZHGLjc20Lak0gqVsNIdMsb+1etWmtWSIq2MkEBSZqzXHXbFL8Ij+dJ5 g3HUn8wZr1iAm+NkHfPX5+qItx0S547XuEw/qWCB0voQMuWT4uTzUvsaE9SydrSCPRFR5NR3zwQh fr6QOaQWJCCzSAzSAzSBzSBzSCyhCE3f/9oACAECAgY/ACZ1bqylGJA/OVZVcfKScBiC3d6u7agB +g09CcyEm5RoGdTrIgku4IQBPENVuv2Q5G4+Wzb7fYgxz17ml/KIi5DFqL//2gAIAQMCBj8ANaAr c9sq/ktoNHfF1I34kYVQRQYlost4FZvofqqPfQogPY4kv//aAAgBAQEGPwBptMlrSGsyEYKZzIFR EBJLH6z+bEx4h/t+wHmse2w/5A81iZiw+c/sB5rGnffl9wPNY8w/5Ac1jVL3z/DYGP8AZxlDH/KH mMTEtfGf79oeYxtrsO1QJnOaQiMgEms/U9rQBafp4uj9gM/5q+FVUDrfYMVKHOIzM50LHUWkR1FP vY2be0LdRCQLcppCQTAsFwVmuJRDn2G6P7DwVTpifEPAJaQahDgiRCSzcSx7TB97Fm8leqtR2/Es zGNO7MqTwEUGzWcae6E/p4X1MhUuo+GEk2PSsmQqZB20hjQe0lnHZWvX/WGItkgZVNeLukWqJnhi y02vCgwrWxxcTNrg9/Rt4TZNaiVZnTW2rCGk0tQokaqq7mtskLTES2BPb+sxtXAES1EEyDAaMGE5 NSTK5sWL1ZjuoIt4NxesO8XgvuLH4LcXc/27EZ/Or4pXm5kqrYU44GImZFZiwoGCkeLSPDxYnqNC ROSa5u2+jVXAwyc4FuibX/QIcz724OsD7wO8Zi1soF3UbttL2QwIGtC68zZr7IVGVjW8bpa9vy2y G3o+rx/6NEeLTW661DlM21MYBLYVqzuq8QgNJPPSjS0+7+Jx4p9IUbRbRi0MGynXbDIewmJ0Nc83 dPLRp3TrazA+xubC8K6camKrF0pPT3W1LXFpbFcZ7LNYlY6fZKFrsVWvTuB2Nhmvf6DTXDhf0g3m 4wkVzO60LC5qv74lsEQ+KSeA/cZisddZFcAWTevEpdebBmwmLk6dU2IElBOkrG5vP1958MMH9xY/ Bbi5+btT3MapmsETEbqOz+d4j17ePOWvSr5/HnLXpV8/j2XLXpV8/jzlr0q+fx5y16VfP485a9Kv n8ectelXz+POWvSr5/BaLdmZ2X551VxGW03X+uL3Mf/Z ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/button_subscribe.jpg /9j/4AAQSkZJRgABAgEASABIAAD/4QimRXhpZgAATU0AKgAAAAgABwESAAMAAAABAAEAAAEaAAUA AAABAAAAYgEbAAUAAAABAAAAagEoAAMAAAABAAIAAAExAAIAAAAUAAAAcgEyAAIAAAAUAAAAhodp AAQAAAABAAAAnAAAAMgAAABIAAAAAQAAAEgAAAABQWRvYmUgUGhvdG9zaG9wIDcuMAAyMDAzOjA3 OjE1IDEwOjExOjQ5AAAAAAOgAQADAAAAAf//AACgAgAEAAAAAQAAAFagAwAEAAAAAQAAAB0AAAAA AAAABgEDAAMAAAABAAYAAAEaAAUAAAABAAABFgEbAAUAAAABAAABHgEoAAMAAAABAAIAAAIBAAQA AAABAAABJgICAAQAAAABAAAHeAAAAAAAAABIAAAAAQAAAEgAAAAB/9j/4AAQSkZJRgABAgEASABI AAD/7QAMQWRvYmVfQ00AAv/uAA5BZG9iZQBkgAAAAAH/2wCEAAwICAgJCAwJCQwRCwoLERUPDAwP FRgTExUTExgRDAwMDAwMEQwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwBDQsLDQ4NEA4OEBQO Dg4UFA4ODg4UEQwMDAwMEREMDAwMDAwRDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDP/AABEI AB0AVgMBIgACEQEDEQH/3QAEAAb/xAE/AAABBQEBAQEBAQAAAAAAAAADAAECBAUGBwgJCgsBAAEF AQEBAQEBAAAAAAAAAAEAAgMEBQYHCAkKCxAAAQQBAwIEAgUHBggFAwwzAQACEQMEIRIxBUFRYRMi cYEyBhSRobFCIyQVUsFiMzRygtFDByWSU/Dh8WNzNRaisoMmRJNUZEXCo3Q2F9JV4mXys4TD03Xj 80YnlKSFtJXE1OT0pbXF1eX1VmZ2hpamtsbW5vY3R1dnd4eXp7fH1+f3EQACAgECBAQDBAUGBwcG BTUBAAIRAyExEgRBUWFxIhMFMoGRFKGxQiPBUtHwMyRi4XKCkkNTFWNzNPElBhaisoMHJjXC0kST VKMXZEVVNnRl4vKzhMPTdePzRpSkhbSVxNTk9KW1xdXl9VZmdoaWprbG1ub2JzdHV2d3h5ent8f/ 2gAMAwEAAhEDEQA/APP8TEZf6rrnurrpZ6ji1ocY3MpADC+pv0rW/nI7GdMaIORef+sN/wDepal2 HTR0nIe0fpDW1rvgbqT/AN9WThYOXn5dWHh1OuyLjtrrbyTz39rWtb73vf7GM/SWexbBjGAyREiI SJMhsNfmbAxiJsHWNUfoyjpu6ftF8eHoN/8AelJ9fTHf9qLwR39Bv/vUjjoXVH2XVMpbYcfHdmWO ZZW6s0VnbbfVeyw0Xtrf+jf6Flj/AFGWV/zldiJV9WOtW2MqbQ0OfiDqILramAYrjAyX2WWMZW39 /wBR2+tNJxmUZmQ4oCoyuIoKIBBBNg6m2j6HTIj7Tf8A9sM/96lIU9LDQ317/j6Df/epWv8Am71n 7Z9i+z/pvR+1bt9fpfZ9vqfa/te/7H9m2/4f1/R3/o9/qKFPQeqXWZFbKmt+yNa7ItssrrqaLC0Y 7vtV1jMVzcnex2K5tv61X+ko9StLLKGWNTnY+bfh3/uoGOA2PTv0a/odMn+kX/8AbDf/AHqTmnpp EDIvB8fQb/71K5h/VjrWZWbKaGta3IOGRdbVS77QAD9lFeVZVY6/X+a2oVXQuqXYuXmCprKenuLM z1LK631uGmyzHusrv3Of+jqZ6f6S79DX+k9iiGDlwbFXE/vdfJXDHa/xQCnpoA/WLyRrPoM/96kV 7+mPYG+veCCDu9Fvb/0KViz6r9bqxBluoaajjjN2ttqdZ9mdG3K+y12OyvQ93ut9L2f4TZ6aFldC 6lhYlWXlNqqqvqZfS119Pqurt/mrWYot+1Oa7/iv39/0LFLH243wyHquO4PzfNFXDEgC+vfqhZh9 PsD7W5F0Ut3vmlgMFzafb+s+79Jaz/raSbE/mM3/AIgf+fsdJR/d8W3Dp8u52+f/AKSuAX1+b9j/ AP/Q5rKs3YGW3sKmn/walZvSM13T+o05jLbaHUuJbbRt9RpI27gy39Hc1u79Lj2bGZVfqY/qV+p6 jNm2rpH2XLnJydvpDcfs9cgepT9H9c93v2LJ9HoOv65lf+wtf/vetrNKJJ34a1uNdP60WzKQs3f2 Sdmr6ydEp6nk2UYr6cTN6Y7p2RbVXXW91r2tFnUG4Fb2YtW+ytrfstWTWz/D+p6n6NWqPrh0urP3 bLxjVdFHR6rTVXY9z27XfabsO637P6e7d+ruvu3/AOE/nPZzvo9C/wC5mV/7C1/+96b0ehf9zMr/ ANha/wD3vVYxwdSdq1/NYTHx+wuxl/WfGu6vXlY9l+NSzBZgvtFdTw/a3ZabOkWPOA3Etbur/Z1V zKK3+nl/zn6CxHr/AEN/7exKsazA6f1g0Ox/Ra2x1Rx7PW1xnW47NuTNj9ld+zF/mK/UYsj0ehf9 zMr/ANha/wD3vTej0L/uZlf+wtf/AL3o8OLSidhX2+j/AJ3yquPj06F2ujfW/E6P0uvFoxPXsq6n 9ubVkhljPR9L0mNbkbRZXm1vDXVZVWMz9/8Am/Ux0OvrPRaul9fwW3Zlz+rvqfRbdXWXj0XHKH2u z7T7rLrXurtta3/ux6f6T7PXlej0Kf6Zlf8AsLX/AO96b0ehf9zMr/2Fr/8Ae9LhxWdTdi/O9P8A nKuNnfftJ6PI+uPTH9JGMxlzrh0hnTDX6Vdf6RpbuyP2lXa7OdjNj+gen6F/+H/nHqj1zr/T+pdK wsalz2XYmFj4rq7MSh259J/SPZ1I2uzqK/3aq6//AD/Ysr0ehf8AczK/9ha//e9L0eg/9zMr/wBh a/8A3vQjHCCCDrenmoGPS9+0kWJ/R83/AIgf+fsdJXsWnonoZm3LyT+iG+cWsED1aPo/r3u9+xJT Xr137HsniF9d+0n/2f/tDU5QaG90b3Nob3AgMy4wADhCSU0EJQAAAAAAEAAAAAAAAAAAAAAAAAAA AAA4QklNA+0AAAAAABAASAAAAAEAAgBIAAAAAQACOEJJTQQmAAAAAAAOAAAAAAAAAAAAAD+AAAA4 QklNBA0AAAAAAAQAAAAeOEJJTQQZAAAAAAAEAAAAHjhCSU0D8wAAAAAACQAAAAAAAAAAAQA4QklN BAoAAAAAAAEAADhCSU0nEAAAAAAACgABAAAAAAAAAAI4QklNA/UAAAAAAEgAL2ZmAAEAbGZmAAYA AAAAAAEAL2ZmAAEAoZmaAAYAAAAAAAEAMgAAAAEAWgAAAAYAAAAAAAEANQAAAAEALQAAAAYAAAAA AAE4QklNA/gAAAAAAHAAAP////////////////////////////8D6AAAAAD///////////////// ////////////A+gAAAAA/////////////////////////////wPoAAAAAP////////////////// //////////8D6AAAOEJJTQQIAAAAAAAQAAAAAQAAAkAAAAJAAAAAADhCSU0EHgAAAAAABAAAAAA4 QklNBBoAAAAAA1UAAAAGAAAAAAAAAAAAAAAdAAAAVgAAABAAYgB1AHQAdABvAG4AXwBzAHUAYgBz AGMAcgBpAGIAZQAAAAEAAAAAAAAAAAAAAAAAAAAAAAAAAQAAAAAAAAAAAAAAVgAAAB0AAAAAAAAA AAAAAAAAAAAAAQAAAAAAAAAAAAAAAAAAAAAAAAAQAAAAAQAAAAAAAG51bGwAAAACAAAABmJvdW5k c09iamMAAAABAAAAAAAAUmN0MQAAAAQAAAAAVG9wIGxvbmcAAAAAAAAAAExlZnRsb25nAAAAAAAA AABCdG9tbG9uZwAAAB0AAAAAUmdodGxvbmcAAABWAAAABnNsaWNlc1ZsTHMAAAABT2JqYwAAAAEA AAAAAAVzbGljZQAAABIAAAAHc2xpY2VJRGxvbmcAAAAAAAAAB2dyb3VwSURsb25nAAAAAAAAAAZv cmlnaW5lbnVtAAAADEVTbGljZU9yaWdpbgAAAA1hdXRvR2VuZXJhdGVkAAAAAFR5cGVlbnVtAAAA CkVTbGljZVR5cGUAAAAASW1nIAAAAAZib3VuZHNPYmpjAAAAAQAAAAAAAFJjdDEAAAAEAAAAAFRv cCBsb25nAAAAAAAAAABMZWZ0bG9uZwAAAAAAAAAAQnRvbWxvbmcAAAAdAAAAAFJnaHRsb25nAAAA VgAAAAN1cmxURVhUAAAAAQAAAAAAAG51bGxURVhUAAAAAQAAAAAAAE1zZ2VURVhUAAAAAQAAAAAA BmFsdFRhZ1RFWFQAAAABAAAAAAAOY2VsbFRleHRJc0hUTUxib29sAQAAAAhjZWxsVGV4dFRFWFQA AAABAAAAAAAJaG9yekFsaWduZW51bQAAAA9FU2xpY2VIb3J6QWxpZ24AAAAHZGVmYXVsdAAAAAl2 ZXJ0QWxpZ25lbnVtAAAAD0VTbGljZVZlcnRBbGlnbgAAAAdkZWZhdWx0AAAAC2JnQ29sb3JUeXBl ZW51bQAAABFFU2xpY2VCR0NvbG9yVHlwZQAAAABOb25lAAAACXRvcE91dHNldGxvbmcAAAAAAAAA CmxlZnRPdXRzZXRsb25nAAAAAAAAAAxib3R0b21PdXRzZXRsb25nAAAAAAAAAAtyaWdodE91dHNl dGxvbmcAAAAAADhCSU0EEQAAAAAAAQEAOEJJTQQUAAAAAAAEAAAAAThCSU0EDAAAAAAHlAAAAAEA AABWAAAAHQAAAQQAAB10AAAHeAAYAAH/2P/gABBKRklGAAECAQBIAEgAAP/tAAxBZG9iZV9DTQAC /+4ADkFkb2JlAGSAAAAAAf/bAIQADAgICAkIDAkJDBELCgsRFQ8MDA8VGBMTFRMTGBEMDAwMDAwR DAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAENCwsNDg0QDg4QFA4ODhQUDg4ODhQRDAwMDAwR EQwMDAwMDBEMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwM/8AAEQgAHQBWAwEiAAIRAQMRAf/d AAQABv/EAT8AAAEFAQEBAQEBAAAAAAAAAAMAAQIEBQYHCAkKCwEAAQUBAQEBAQEAAAAAAAAAAQAC AwQFBgcICQoLEAABBAEDAgQCBQcGCAUDDDMBAAIRAwQhEjEFQVFhEyJxgTIGFJGhsUIjJBVSwWIz NHKC0UMHJZJT8OHxY3M1FqKygyZEk1RkRcKjdDYX0lXiZfKzhMPTdePzRieUpIW0lcTU5PSltcXV 5fVWZnaGlqa2xtbm9jdHV2d3h5ent8fX5/cRAAICAQIEBAMEBQYHBwYFNQEAAhEDITESBEFRYXEi EwUygZEUobFCI8FS0fAzJGLhcoKSQ1MVY3M08SUGFqKygwcmNcLSRJNUoxdkRVU2dGXi8rOEw9N1 4/NGlKSFtJXE1OT0pbXF1eX1VmZ2hpamtsbW5vYnN0dXZ3eHl6e3x//aAAwDAQACEQMRAD8A8/xM Rl/quue6uulnqOLWhxjcykAML6m/Stb+cjsZ0xog5F5/6w3/AN6lqXYdNHSch7R+kNbWu+BupP8A 31ZOFg5efl1YeHU67IuO2utvJPPf2ta1vve9/sYz9JZ7FsGMYDJESIhIkyGw1+ZsDGImwdY1R+jK Om7p+0Xx4eg3/wB6Un19Md/2ovBHf0G/+9SOOhdUfZdUylthx8d2ZY5llbqzRWdtt9V7LDRe2t/6 N/oWWP8AUZZX/OV2IlX1Y61bYyptDQ5+IOogutqYBiuMDJfZZYxlbf3/AFHb600nGZRmZDigKjK4 igogEEE2DqbaPodMiPtN/wD2wz/3qUhT0sNDfXv+PoN/96la/wCbvWftn2L7P+m9H7Vu31+l9n2+ p9r+17/sf2bb/h/X9Hf+j3+ooU9B6pdZkVsqa37I1rsi2yyuuposLRju+1XWMxXNyd7HYrm2/rVf 6Sj1K0ssoZY1Odj5t+Hf+6gY4DY9O/Rr+h0yf6Rf/wBsN/8AepOaemkQMi8Hx9Bv/vUrmH9WOtZl Zspoa1rcg4ZF1tVLvtAAP2UV5VlVjr9f5rahVdC6pdi5eYKmsp6e4szPUsrrfW4abLMe6yu/c5/6 Opnp/pLv0Nf6T2KIYOXBsVcT+918lcMdr/FAKemgD9YvJGs+gz/3qRXv6Y9gb694IIO70W9v/QpW LPqv1urEGW6hpqOOM3a22p1n2Z0bcr7LXY7K9D3e630vZ/hNnpoWV0LqWFiVZeU2qqq+pl9LXX0+ q6u3+atZii37U5rv+K/f3/QsUsfbjfDIeq47g/N80VcMSAL69+qFmH0+wPtbkXRS3e+aWAwXNp9v 6z7v0lrP+tpJsT+Yzf8AiB/5+x0lH93xbcOny7nb5/8ApK4BfX5v2P8A/9DmsqzdgZbewqaf/BqV m9IzXdP6jTmMttodS4lttG31GkjbuDLf0dzW7v0uPZsZlV+pj+pX6nqM2baukfZcucnJ2+kNx+z1 yB6lP0f1z3e/Ysn0eg6/rmV/7C1/+962s0oknfhrW410/rRbMpCzd/ZJ2avrJ0SnqeTZRivpxM3p junZFtVddb3Wva0WdQbgVvZi1b7K2t+y1ZNbP8P6nqfo1ao+uHS6s/dsvGNV0UdHqtNVdj3Pbtd9 puw7rfs/p7t36u6+7f8A4T+c9nO+j0L/ALmZX/sLX/73pvR6F/3Myv8A2Fr/APe9VjHB1J2rX81h MfH7C7GX9Z8a7q9eVj2X41LMFmC+0V1PD9rdlps6RY84DcS1u6v9nVXMorf6eX/OfoLEev8AQ3/t 7EqxrMDp/WDQ7H9FrbHVHHs9bXGdbjs25M2P2V37MX+Yr9RiyPR6F/3Myv8A2Fr/APe9N6PQv+5m V/7C1/8Avejw4tKJ2Ffb6P8AnfKq4+PToXa6N9b8To/S68WjE9eyrqf25tWSGWM9H0vSY1uRtFle bW8NdVlVYzP3/wCb9THQ6+s9Fq6X1/BbdmXP6u+p9Ft1dZePRccofa7PtPusute6u21rf+7Hp/pP s9eV6PQp/pmV/wCwtf8A73pvR6F/3Myv/YWv/wB70uHFZ1N2L870/wCcq42d9+0no8j649Mf0kYz GXOuHSGdMNfpV1/pGlu7I/aVdrs52M2P6B6foX/4f+ceqPXOv9P6l0rCxqXPZdiYWPiursxKHbn0 n9I9nUja7Oor/dqrr/8AP9iyvR6F/wBzMr/2Fr/970vR6D/3Myv/AGFr/wDe9CMcIIIOt6eagY9L 37SRYn9Hzf8AiB/5+x0lexaeiehmbcvJP6Ib5xawQPVo+j+ve737ElNevXfseyeIX137Sf/ZOEJJ TQQhAAAAAABVAAAAAQEAAAAPAEEAZABvAGIAZQAgAFAAaABvAHQAbwBzAGgAbwBwAAAAEwBBAGQA bwBiAGUAIABQAGgAbwB0AG8AcwBoAG8AcAAgADcALgAwAAAAAQA4QklNBAYAAAAAAAcAAQEBAAEB AP/hEkhodHRwOi8vbnMuYWRvYmUuY29tL3hhcC8xLjAvADw/eHBhY2tldCBiZWdpbj0n77u/JyBp ZD0nVzVNME1wQ2VoaUh6cmVTek5UY3prYzlkJz8+Cjw/YWRvYmUteGFwLWZpbHRlcnMgZXNjPSJD UiI/Pgo8eDp4YXBtZXRhIHhtbG5zOng9J2Fkb2JlOm5zOm1ldGEvJyB4OnhhcHRrPSdYTVAgdG9v bGtpdCAyLjguMi0zMywgZnJhbWV3b3JrIDEuNSc+CjxyZGY6UkRGIHhtbG5zOnJkZj0naHR0cDov L3d3dy53My5vcmcvMTk5OS8wMi8yMi1yZGYtc3ludGF4LW5zIycgeG1sbnM6aVg9J2h0dHA6Ly9u cy5hZG9iZS5jb20vaVgvMS4wLyc+CgogPHJkZjpEZXNjcmlwdGlvbiBhYm91dD0ndXVpZDo0Yjhj NTllOC1iNmE0LTExZDctOWRkYi1hY2JjZTJhMjY5OTEnCiAgeG1sbnM6eGFwTU09J2h0dHA6Ly9u cy5hZG9iZS5jb20veGFwLzEuMC9tbS8nPgogIDx4YXBNTTpEb2N1bWVudElEPmFkb2JlOmRvY2lk OnBob3Rvc2hvcDo0YjhjNTllNC1iNmE0LTExZDctOWRkYi1hY2JjZTJhMjY5OTE8L3hhcE1NOkRv Y3VtZW50SUQ+CiA8L3JkZjpEZXNjcmlwdGlvbj4KCjwvcmRmOlJERj4KPC94OnhhcG1ldGE+CiAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAK ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg IAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAog ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAo8P3hwYWNrZXQg ZW5kPSd3Jz8+/+4AIUFkb2JlAGSAAAAAAQMAEAMCAwYAAAAAAAAAAAAAAAD/2wCEAAwICAgJCAwJ CQwRCwoLERUPDAwPFRgTExUTExgRDAwMDAwMEQwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwB DQsLDQ4NEA4OEBQODg4UFA4ODg4UEQwMDAwMEREMDAwMDAwRDAwMDAwMDAwMDAwMDAwMDAwMDAwM DAwMDAwMDP/CABEIAB0AVgMBIgACEQEDEQH/xACuAAACAwEBAQAAAAAAAAAAAAADBQABBAIGBwEA AwEBAQAAAAAAAAAAAAAAAAEDAgQFEAABBAIDAQEBAQAAAAAAAAAFAQIDBAATERIGFDQhFhEAAgIA AwYCBwcFAQAAAAAAAgMBBAASExEiIxTUBTSUIUEyUjNDJDFRcXODk7PBQqNkFYQSAAEDAwMBBgcA AAAAAAAAAAEAEQIhMUFREjJxYYGRoSKiscFScpKyA//aAAwDAQECEQMRAAAA+fnaKfYv1Dky8PWr gWe9gpADHFUDKkxotcqejTnV52ubDiKKY6GpgejwqogM3y2v/9oACAECAAEFAFa1iKsaulcyVqQV 0VutufPFkzmqqtgzrFnWLlrYUXn+/wD/2gAIAQMAAQUASNGOVEVEjYmdW51aqdE5c5OVVuctzlvP Lc7Jz//aAAgBAQABBQCpVZPjGDGp1G9nxDHZoGcJCLRukZysQ1USEaiSPGPYymPkSanDAIpUbd+2 0EUfJF5g1LJ/nTP2QgSk0lPzBq5HECKTVJPLm4qloESp1Kn57UnagIuuHkYvSBIScHsBcV+36etM XX0AN+BvX1A4uMyFiF2PYjHiTh8eSFVPzyxB/l0gc0gs0gc0gs0gc0gedILNIHNIHKsITR//2gAI AQICBj8A/pESIhIkyFhXkozMhugGjJ4hgts5uOV9t/tThnifqz0R2yHqeNweXKKbbTjc25/sjfa1 Xi2O2KqTbPxQYmwbx9Hu4o1LuH6vT3IEGr06rN9Dov/aAAgBAwIGPwBwaxZj3Iglwal1Q41wmfzQ D51ys8vki7/jJZ8Cs4wUb30Ko99Cs30lov/aAAgBAQEGPwBpOMlrSGoUiMEWzMCYiAk1D7TR/uxs mw+f0B6rG3mH7Pu0B6nHiHxMevQHqsbOZf8AsD1WIjmH/joD1WPEP/YHqsbIsPifv0B6rEfUPmY9 O3QHqsQOu+JiYnNoj6v/AFYNo2HbEjnPakInZJCnd+p3uI0P08WDGOJKxEvwlyZ/phVOmonWHTlW sftmft9e6IiO+ZnuAHEZuYcoEiya9crjCBiyXNdc5WvU8GSh4rPhnoMM9QGL+ItmAUKBzHUjuMST VBEVSnZFk2MYALH39Qs4Y5Ll+No81mzr0uXy6vN83n5Plsvz9fRz8PPqbmLCwUI8oIlYaxi1qGGS MILmnMCqQ2c4FVMW/VL4iNReJYlAiI2JpzDmqSXMRETysLtMUwn+n4WXFu5ChBPbykLmoxazWUej Iyu5i35iPhqDT4juCviYi2SBlU14u5RaomcsWzLa5UGFa0N7ebpbnzMmnhVu0KlKeoHpEnp1SW34 TQqw3miEvyvfz+wzF38iP5q+LY+qFDP+ZOE3Aa1BJKZFqMuoMzGXNAN4bhHNxa7MgWl6lfUXqagW WIqmmpd7YXbrDVLWsyaYDDO4DQWYVVZ2LEeVVZWHz9TPw8Zsj4rK7LHZ1NlS2GRjlLmXU3N5fTzZ vpye7P8AM+JuLtV2PrJCiFE2wtRweUcjZZ2hhzQGo0cy/wDnKcCFnp2/icBnfqiqzaHb+8Sgq+iI sJU12avprE2uGWzxCyLfkq/AXqBhdVFTXYrufPCqzAMDR0tIBGxlhi7qzgSVaVWD3/h6lfHf6Iuu OPu5qNDXLXJxolNqJts5neY5pktrRH/Y0+Jy64rADidHaA7ZK9Ja+IMjmsf9JbSvFWHZ4DT0H/P+ IeKVZJGDqlKvUJbKiCzGmeIYdylpXUL91S1/zsxd/Ij+avi3ts2culGaeXXtiNRPs/Wb2/kxP1lr yq+vx4y15VfX48Za8qvr8eMteVX1+PGWvKr6/HjLXlV9fjxlryq+vx4y15VfX48Za8qvr8XMtuzP CjPtqriYjVR7P129v5Mf/9k= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/button_register.jpg /9j/4AAQSkZJRgABAgEASABIAAD/4QhuRXhpZgAATU0AKgAAAAgABwESAAMAAAABAAEAAAEaAAUA AAABAAAAYgEbAAUAAAABAAAAagEoAAMAAAABAAIAAAExAAIAAAAUAAAAcgEyAAIAAAAUAAAAhodp AAQAAAABAAAAnAAAAMgAAABIAAAAAQAAAEgAAAABQWRvYmUgUGhvdG9zaG9wIDcuMAAyMDAzOjA3 OjE1IDEwOjEyOjI1AAAAAAOgAQADAAAAAf//AACgAgAEAAAAAQAAAFegAwAEAAAAAQAAAB0AAAAA AAAABgEDAAMAAAABAAYAAAEaAAUAAAABAAABFgEbAAUAAAABAAABHgEoAAMAAAABAAIAAAIBAAQA AAABAAABJgICAAQAAAABAAAHQAAAAAAAAABIAAAAAQAAAEgAAAAB/9j/4AAQSkZJRgABAgEASABI AAD/7QAMQWRvYmVfQ00AAv/uAA5BZG9iZQBkgAAAAAH/2wCEAAwICAgJCAwJCQwRCwoLERUPDAwP FRgTExUTExgRDAwMDAwMEQwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwBDQsLDQ4NEA4OEBQO Dg4UFA4ODg4UEQwMDAwMEREMDAwMDAwRDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDP/AABEI AB0AVwMBIgACEQEDEQH/3QAEAAb/xAE/AAABBQEBAQEBAQAAAAAAAAADAAECBAUGBwgJCgsBAAEF AQEBAQEBAAAAAAAAAAEAAgMEBQYHCAkKCxAAAQQBAwIEAgUHBggFAwwzAQACEQMEIRIxBUFRYRMi cYEyBhSRobFCIyQVUsFiMzRygtFDByWSU/Dh8WNzNRaisoMmRJNUZEXCo3Q2F9JV4mXys4TD03Xj 80YnlKSFtJXE1OT0pbXF1eX1VmZ2hpamtsbW5vY3R1dnd4eXp7fH1+f3EQACAgECBAQDBAUGBwcG BTUBAAIRAyExEgRBUWFxIhMFMoGRFKGxQiPBUtHwMyRi4XKCkkNTFWNzNPElBhaisoMHJjXC0kST VKMXZEVVNnRl4vKzhMPTdePzRpSkhbSVxNTk9KW1xdXl9VZmdoaWprbG1ub2JzdHV2d3h5ent8f/ 2gAMAwEAAhEDEQA/AOCxMZlrbHW2OZXQze4taHOMuZSAGF1bfpWt/ORPS6Z3yLyP+Ib/AO9SWJtO NnOB/wAC0AR/w1HdLp3TczqmZXg4NfrZN27069wbO1rrHe+1zGe1jHfScr+HBHgkckTEgm7PDp3Z hEEWSsaOkH/DZH/bLP8A3pU2N6XWIrvvbPM0tP8A7tBWWfVjrVmXi4lVDbbc9r3Yjq7an1WCrd63 p5Vdj8XdT6bvVZ6u/wD7cYhV9C6lblHEobVda2p173VX02VMqZPqW35Vdr8WhrNvu9e1n+D/ANJW pODCRRlYGtGVivJPBHv+KMfs6fdfe7y9Bo/92k7v2W6IvvEf8Cz/AN6UXG+rvVsvPb0/HqZbk2MN tTW3VFljBo52Pf6v2fJ2uZY13oWP2ejf/oLPTbH6B1TJrttopD6qbfs5eLK9r7Yc4Y+I71Nude7Z 7KsP17H/AKP0/wCcYmyw4Jb1p/WrdXBHv+LCelBm0XXg+Pot/wDelPW/pjeb73f9Zb/70qf/ADd6 p+zv2pFP2Lj1vtOP9Lb6/oen6/q/afS932XZ9p/4NTy/qz1jDy6sHJrqbmXWsoZjDIodb6lv80H1 VXPfU2yW/pbWsr99fv8A0iA5flttOv6Xbf8ASVwx7/iibZ0wPLjdefL0Wf8AvQjVVYWYbPs73l1b N5a+trQW7m1fTbbb7t1n7qD1HoPVOm1erl0tbV6rsdz67a7WtuYN1mPc7Gsu9K//AIK3Y/8AzHov 1fqF1+TWTAdQZPwspP8ABCXLYTCUoDWtCCTqtlGIBIOyD0dtxZpBIH3lJIBpzHe79H6g93kCks2t VnR//9DjaGVswM1rfpGppny9ahH+qfV8bov1gxep5TXvox/U3MrALzvqspbt3urb9Kz95Tx6ejeh lxl5RBpG4nGrBA9Wnj9d9z9+xU/R6F/3Myv/AGFr/wDe9bWeUZGViUYka2CPTTMDHhIF14AvQ9M+ uOBVndG6jmVW1W9KbdTZjYldbcd7LWWj7XRQH0Mxst91365tZ6N+z1K7K/T9BU8Lr/T8XPy3PL7c bO6fdgPtqxcfFfWbdRa3DxLfs+Rtcxv0r6X2b/8AgGeplej0L/uZlf8AsLX/AO96Xo9C/wC5mV/7 C1/+96rcOHXXp+F/98q4eP2F3Onde+q3TPrPhdWwsfIoxMXHc26prAXWZDm202WMbfmX+hQ5lzXN /Wb/AOb9P/h1U6J1npeBVkYmaLs3Ac+x7cJ9dRruJrfRj2Fz3ut6Tks37rcrDsybHs9Ov/tP+nzv R6FH9Myv/YWv/wB70/o9C/7mZX/sLX/73pxjCiCZbD5v+b/3Srj1vp0Kf9r43/NP9ibX/af2h9s3 w30/T9H7Pt3bt/qb/wDg9mz/AAi2etfWzpef9YsbrFPqiqrLx730OxMeu0MpDBZ/lCu5+TkOds9l F/6H3/zn6Ctc96PQv+5mV/7C1/8Avel6PQv+5mV/7C1/+96BGK9Tr6un73DxpuN9evQ/V1uv/WbE 61h5FBrfjPZm25WKKmMZXey489SqY5n67jVBjKsxvrb/ANJXZ/3IQvqRi/berW48kb8ayI8QWOH5 FninoXbMyv8A2Fr/APe9dL/i9r6c36xA4mRfbb6NnstoZW3b7d36SvKyP/PaPpGKQx2dDWnp4lky PbkBeoPQ19rygof+0XYhB9UXCrbGm4ugJLq86voh+vdbq77W2faqd9TaWupL97fpXnJY7a7/AMLJ LO4TfTf96Ky/TtrT/9n/7Q0UUGhvdG9zaG9wIDMuMAA4QklNBCUAAAAAABAAAAAAAAAAAAAAAAAA AAAAOEJJTQPtAAAAAAAQAEgAAAABAAIASAAAAAEAAjhCSU0EJgAAAAAADgAAAAAAAAAAAAA/gAAA OEJJTQQNAAAAAAAEAAAAHjhCSU0EGQAAAAAABAAAAB44QklNA/MAAAAAAAkAAAAAAAAAAAEAOEJJ TQQKAAAAAAABAAA4QklNJxAAAAAAAAoAAQAAAAAAAAACOEJJTQP1AAAAAABIAC9mZgABAGxmZgAG AAAAAAABAC9mZgABAKGZmgAGAAAAAAABADIAAAABAFoAAAAGAAAAAAABADUAAAABAC0AAAAGAAAA AAABOEJJTQP4AAAAAABwAAD/////////////////////////////A+gAAAAA//////////////// /////////////wPoAAAAAP////////////////////////////8D6AAAAAD///////////////// ////////////A+gAADhCSU0ECAAAAAAAEAAAAAEAAAJAAAACQAAAAAA4QklNBB4AAAAAAAQAAAAA OEJJTQQaAAAAAANTAAAABgAAAAAAAAAAAAAAHQAAAFcAAAAPAGIAdQB0AHQAbwBuAF8AcgBlAGcA aQBzAHQAZQByAAAAAQAAAAAAAAAAAAAAAAAAAAAAAAABAAAAAAAAAAAAAABXAAAAHQAAAAAAAAAA AAAAAAAAAAABAAAAAAAAAAAAAAAAAAAAAAAAABAAAAABAAAAAAAAbnVsbAAAAAIAAAAGYm91bmRz T2JqYwAAAAEAAAAAAABSY3QxAAAABAAAAABUb3AgbG9uZwAAAAAAAAAATGVmdGxvbmcAAAAAAAAA AEJ0b21sb25nAAAAHQAAAABSZ2h0bG9uZwAAAFcAAAAGc2xpY2VzVmxMcwAAAAFPYmpjAAAAAQAA AAAABXNsaWNlAAAAEgAAAAdzbGljZUlEbG9uZwAAAAAAAAAHZ3JvdXBJRGxvbmcAAAAAAAAABm9y aWdpbmVudW0AAAAMRVNsaWNlT3JpZ2luAAAADWF1dG9HZW5lcmF0ZWQAAAAAVHlwZWVudW0AAAAK RVNsaWNlVHlwZQAAAABJbWcgAAAABmJvdW5kc09iamMAAAABAAAAAAAAUmN0MQAAAAQAAAAAVG9w IGxvbmcAAAAAAAAAAExlZnRsb25nAAAAAAAAAABCdG9tbG9uZwAAAB0AAAAAUmdodGxvbmcAAABX AAAAA3VybFRFWFQAAAABAAAAAAAAbnVsbFRFWFQAAAABAAAAAAAATXNnZVRFWFQAAAABAAAAAAAG YWx0VGFnVEVYVAAAAAEAAAAAAA5jZWxsVGV4dElzSFRNTGJvb2wBAAAACGNlbGxUZXh0VEVYVAAA AAEAAAAAAAlob3J6QWxpZ25lbnVtAAAAD0VTbGljZUhvcnpBbGlnbgAAAAdkZWZhdWx0AAAACXZl cnRBbGlnbmVudW0AAAAPRVNsaWNlVmVydEFsaWduAAAAB2RlZmF1bHQAAAALYmdDb2xvclR5cGVl bnVtAAAAEUVTbGljZUJHQ29sb3JUeXBlAAAAAE5vbmUAAAAJdG9wT3V0c2V0bG9uZwAAAAAAAAAK bGVmdE91dHNldGxvbmcAAAAAAAAADGJvdHRvbU91dHNldGxvbmcAAAAAAAAAC3JpZ2h0T3V0c2V0 bG9uZwAAAAAAOEJJTQQRAAAAAAABAQA4QklNBBQAAAAAAAQAAAABOEJJTQQMAAAAAAdcAAAAAQAA AFcAAAAdAAABCAAAHegAAAdAABgAAf/Y/+AAEEpGSUYAAQIBAEgASAAA/+0ADEFkb2JlX0NNAAL/ 7gAOQWRvYmUAZIAAAAAB/9sAhAAMCAgICQgMCQkMEQsKCxEVDwwMDxUYExMVExMYEQwMDAwMDBEM DAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMAQ0LCw0ODRAODhAUDg4OFBQODg4OFBEMDAwMDBER DAwMDAwMEQwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAz/wAARCAAdAFcDASIAAhEBAxEB/90A BAAG/8QBPwAAAQUBAQEBAQEAAAAAAAAAAwABAgQFBgcICQoLAQABBQEBAQEBAQAAAAAAAAABAAID BAUGBwgJCgsQAAEEAQMCBAIFBwYIBQMMMwEAAhEDBCESMQVBUWETInGBMgYUkaGxQiMkFVLBYjM0 coLRQwclklPw4fFjczUWorKDJkSTVGRFwqN0NhfSVeJl8rOEw9N14/NGJ5SkhbSVxNTk9KW1xdXl 9VZmdoaWprbG1ub2N0dXZ3eHl6e3x9fn9xEAAgIBAgQEAwQFBgcHBgU1AQACEQMhMRIEQVFhcSIT BTKBkRShsUIjwVLR8DMkYuFygpJDUxVjczTxJQYWorKDByY1wtJEk1SjF2RFVTZ0ZeLys4TD03Xj 80aUpIW0lcTU5PSltcXV5fVWZnaGlqa2xtbm9ic3R1dnd4eXp7fH/9oADAMBAAIRAxEAPwDgsTGZ a2x1tjmV0M3uLWhzjLmUgBhdW36VrfzkT0umd8i8j/iG/wDvUlibTjZzgf8AAtAEf8NR3S6d03M6 pmV4ODX62Tdu9OvcGzta6x3vtcxntYx30nK/hwR4JHJExIJuzw6d2YRBFkrGjpB/w2R/2yz/AN6V Njel1iK772zzNLT/AO7QVln1Y61Zl4uJVQ223Pa92I6u2p9Vgq3et6eVXY/F3U+m71Werv8A+3GI VfQupW5RxKG1XWtqde91V9NlTKmT6lt+VXa/Foazb7vXtZ/g/wDSVqTgwkUZWBrRlYryTwR7/ijH 7On3X3u8vQaP/dpO79luiL7xH/As/wDelFxvq71bLz29Px6mW5NjDbU1t1RZYwaOdj3+r9nydrmW Nd6Fj9no3/6Cz02x+gdUya7baKQ+qm37OXiyva+2HOGPiO9TbnXu2eyrD9ex/wCj9P8AnGJssOCW 9af1q3VwR7/iwnpQZtF14Pj6Lf8A3pT1v6Y3m+93/WW/+9Kn/wA3eqfs79qRT9i49b7Tj/S2+v6H p+v6v2n0vd9l2faf+DU8v6s9Yw8urBya6m5l1rKGYwyKHW+pb/NB9VVz31Nslv6W1rK/fX7/ANIg OX5bbTr+l23/AElcMe/4om2dMDy43Xny9Fn/AL0I1VWFmGz7O95dWzeWvra0Fu5tX0222+7dZ+6g 9R6D1TptXq5dLW1eq7Hc+u2u1rbmDdZj3OxrLvSv/wCCt2P/AMx6L9X6hdfk1kwHUGT8LKT/AAQl y2EwlKA1rQgk6rZRiASDsg9HbcWaQSB95SSAacx3u/R+oPd5ApLNrVZ0f//Q42hlbMDNa36RqaZ8 vWoR/qn1fG6L9YMXqeU176Mf1NzKwC876rKW7d7q2/Ss/eU8eno3oZcZeUQaRuJxqwQPVp4/Xfc/ fsVP0ehf9zMr/wBha/8A3vW1nlGRlYlGJGtgj00zAx4SBdeAL0PTPrjgVZ3Ruo5lVtVvSm3U2Y2J XW3Hey1lo+10UB9DMbLfdd+ubWejfs9Suyv0/QVPC6/0/Fz8tzy+3Gzun3YD7asXHxX1m3UWtw8S 37PkbXMb9K+l9m//AIBnqZXo9C/7mZX/ALC1/wDvel6PQv8AuZlf+wtf/veq3Dh116fhf/fKuHj9 hdzp3Xvqt0z6z4XVsLHyKMTFx3NuqawF1mQ5ttNljG35l/oUOZc1zf1m/wDm/T/4dVOidZ6XgVZG Jmi7NwHPse3CfXUa7ia30Y9hc97rek5LN+63Kw7Mmx7PTr/7T/p870ehR/TMr/2Fr/8Ae9P6PQv+ 5mV/7C1/+96cYwogmWw+b/m/90q49b6dCn/a+N/zT/Ym1/2n9ofbN8N9P0/R+z7d27f6m/8A4PZs /wAItnrX1s6Xn/WLG6xT6oqqy8e99DsTHrtDKQwWf5Qrufk5DnbPZRf+h9/85+grXPej0L/uZlf+ wtf/AL3pej0L/uZlf+wtf/vegRivU6+rp+9w8abjfXr0P1dbr/1mxOtYeRQa34z2ZtuViipjGV3s uPPUqmOZ+u41QYyrMb62/wDSV2f9yEL6kYv23q1uPJG/GsiPEFjh+RZ4p6F2zMr/ANha/wD3vXS/ 4va+nN+sQOJkX22+jZ7LaGVt2+3d+krysj/z2j6RikMdnQ1p6eJZMj25AXqD0Nfa8oKH/tF2IQfV Fwq2xpuLoCS6vOr6Ifr3W6u+1tn2qnfU2lrqS/e36V5yWO2u/wDCySzuE303/eisv07a0//ZOEJJ TQQhAAAAAABVAAAAAQEAAAAPAEEAZABvAGIAZQAgAFAAaABvAHQAbwBzAGgAbwBwAAAAEwBBAGQA bwBiAGUAIABQAGgAbwB0AG8AcwBoAG8AcAAgADcALgAwAAAAAQA4QklNBAYAAAAAAAcAAQEBAAEB AP/hEkhodHRwOi8vbnMuYWRvYmUuY29tL3hhcC8xLjAvADw/eHBhY2tldCBiZWdpbj0n77u/JyBp ZD0nVzVNME1wQ2VoaUh6cmVTek5UY3prYzlkJz8+Cjw/YWRvYmUteGFwLWZpbHRlcnMgZXNjPSJD UiI/Pgo8eDp4YXBtZXRhIHhtbG5zOng9J2Fkb2JlOm5zOm1ldGEvJyB4OnhhcHRrPSdYTVAgdG9v bGtpdCAyLjguMi0zMywgZnJhbWV3b3JrIDEuNSc+CjxyZGY6UkRGIHhtbG5zOnJkZj0naHR0cDov L3d3dy53My5vcmcvMTk5OS8wMi8yMi1yZGYtc3ludGF4LW5zIycgeG1sbnM6aVg9J2h0dHA6Ly9u cy5hZG9iZS5jb20vaVgvMS4wLyc+CgogPHJkZjpEZXNjcmlwdGlvbiBhYm91dD0ndXVpZDo0Yjhj NTllYS1iNmE0LTExZDctOWRkYi1hY2JjZTJhMjY5OTEnCiAgeG1sbnM6eGFwTU09J2h0dHA6Ly9u cy5hZG9iZS5jb20veGFwLzEuMC9tbS8nPgogIDx4YXBNTTpEb2N1bWVudElEPmFkb2JlOmRvY2lk OnBob3Rvc2hvcDo0YjhjNTllMy1iNmE0LTExZDctOWRkYi1hY2JjZTJhMjY5OTE8L3hhcE1NOkRv Y3VtZW50SUQ+CiA8L3JkZjpEZXNjcmlwdGlvbj4KCjwvcmRmOlJERj4KPC94OnhhcG1ldGE+CiAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAK ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg IAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAog ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgCiAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgIAogICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgCiAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAKICAgICAgICAg ICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgICAgIAo8P3hwYWNrZXQg ZW5kPSd3Jz8+/+4AIUFkb2JlAGSAAAAAAQMAEAMCAwYAAAAAAAAAAAAAAAD/2wCEAAwICAgJCAwJ CQwRCwoLERUPDAwPFRgTExUTExgRDAwMDAwMEQwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwMDAwB DQsLDQ4NEA4OEBQODg4UFA4ODg4UEQwMDAwMEREMDAwMDAwRDAwMDAwMDAwMDAwMDAwMDAwMDAwM DAwMDAwMDP/CABEIAB0AVwMBIgACEQEDEQH/xAC3AAABBQEAAAAAAAAAAAAAAAADAAECBQYEAQAC AwEAAAAAAAAAAAAAAAABAgADBQQQAAEEAQQBBQEAAAAAAAAAAAUBAgMEABESEwYVIUEiFBYHEQAC AgADBAYFBw0BAAAAAAACAwEEABITESIU1CEyI2OUBTFhMyQ0UUJDU5PEFUFxkcFSkrJzg7NEVHQl EgABAwMCAwgDAAAAAAAAAAABABECITFBoRIQUSJhcZGxQlLCAzJiov/aAAwDAQECEQMRAAAAwREu +5p9IrCNyssg5JCCMEoUCSzUmefJu2aDjqlzS85K52h7nPIG2FX6Ypk1q1nJ/9oACAECAAEFAIYG 7NkKo6GB2JXrY6tCrNPWdzXLthxWs0VItfikW1df/9oACAEDAAEFAEaipsbmxubW45rUT2RW7dWZ q3NW6vVFj1+P/9oACAEBAAEFAKlZkzeIZiwCFxjRcaJ47V3i3ZqKRjHjG42QYj4oqVxeHbNU2rWH DbhS4zrBqS3GCJS26/XS1u/XAlLMf50p4631kxTtkQJQbH1+JJp0Rq3IGMZQ6mXrBewDO40Ir1I+ Pq3xx7qwzs4QyLoReXrfkzXbBd/sR/s1Q1T6RV+6WSB/ka8Ib6/CCzhA5wgs4QWnCCzhA5wgsSEF n89jGt7DejCL3v8A/9oACAECAgY/AJH7ImJBLudtOaYycCrGThu5Van7NdNTPq5X9SlKAq1CCTXh LcJRiRVwR0sjXGjn5IgmVh+X8/JVNerHu271IfW5oWp07li/uiv/2gAIAQMCBj8AclX1V9VfVGQN uBAduwFZ8CqvjBWc4KkA9QcHzVsL/9oACAEBAQY/AGE1hAtAZzkRginaQJiICSWPWYPzsdNh8x/I Hmse2sfYhzGNi3vHb6dqRn71GN6w8vVoDH3rEbHvjZ3IczjZDnxPy6I8zjpe8v6I8ziSlz59WiHM YZw5nJLHPImsRiRzCrri1u9mb+ziQ6NkzEfpnF6Yn6EYiNnfI/LhdGivWsu26a9sDtyiTC32EAbo AXzsVaikC1t8TKoS2qNTIVm1tO0th1cydMtUNXP9oGJqIFTmionmSnpYoFBt1GvtLadVAhl3tdof R/WLwPl9dQNssCWqEXKkGBHQRV36vD2cpAwS0GHk0X/UM03NQkTUlvDycMXlNuwiivULUy3nlk3F U9dh9np+0Xj8U2J4L0a3E1+tl19DT19XidLe4XJxPd4VSsrUNxzQQFaLCCbqN9jnUtxmoT2j2rRB e+vf7TGrbSIr1Srka2raIuCMzK7irMdpP7puQ/3MWVzOyJrztn8zEz+rBb3Z6kb3qicXRHrSoZ2+ rWRir5naEzRX1MwLiJOc6mJHLnJY9Zg/Ox5N5jcU1TfKhcllaotY1zBoN97QiDQFa2bne+ZQ0X5N RbF6ehi2Ryba17y91A2qq16prlvTDRp1G8PYykA9Z6TZn7gM9LzalXsIqVa5C5QhEyywQtSxgC+4 /QQQOEh95f1NPv8AFipch12gRsMaRrVK3TKzRXZJGZN8pshnzNtU2WWGGmv/AB+3/BMp8T+IcZn2 Dp6ejw+XNmz6mfu8mT6TFbzhGrClW67zQVSutsAmA1P/AEFuOzYIsm4h/Y7/ALTsF4sIlZ1jC621 VhQAC3g6fT5koCD32sqBBVwdbP2i2f7GG1tsxnrM2bPlGQKP4cFUmJ1YdCsuzozSWyMXNlu1MSqM 0zWXExGqn0e/bx58mPjLXhV8/j4y14VfP4+MteFXz+PjLXhV8/j4y14VfP4+MteFXz+PjLXhV8/j ouWvCr5/ETUsPa3RZuNQCxy7ubtF2rH9vCyW9os4pOdQpEkyeces+bIFlL/mx//Z ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/advancedsrch.gif R0lGODlhGAAaAMQAAMzM/////zMAZohxxpmZmeLi4rau7MfF+7u28bCm52YzmZOAz///AJmZANDQ 0KqqqpmI1HZat8bE+rq08IJpwbix7o14yqqf45J/z76x3fX19ayi5a+m5wAAAAAAAAAAACH5BAAA AAAALAAAAAAYABoAQAXHICCOZGmOQhAQg1AU6iCrhbAgZboObD+oAgpEwFA0BInDaclcCgQE2hOh NOl6UAcMRiA8MZMSAiIrm8sQHOCQWCySzThKpdJAY79A7WZVsaBbZVIDBjl+PIhPikRGSBJzdJGR AoRsjDZqcpqbnIsCVEyeT1qSAUhVJDpADnp0eaYXqCKqplEFeXk1hIaTBFutNRkWFbyTUARaT40b srSSD9ACEYxHHI8AzqWmAwkJjAqnouKUhZbSNwcIBuvs7eugIunwnPT0IQA7 ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/help.gif R0lGODlhEQAaALMAAMzM/////zMAZsfF+7u28ZOAz7au7IhxxrCm53Zat6qf44JpwY14ywAAAAAA AAAAACH5BAAAAAAALAAAAAARABoAQARrEMhJ6xQh6x0EGsCAcZywKKClruxFCqMmHMY0EEpx7IVC pK0grCT4uWSZoQwVI21mtQFCKRMkGJ+gdstVwb5GS7OUlTS/zwIBME6e1WOqjEY4xxNqQN2ZxK8l UgVfMAkLBWUVNwaLYV2OFhEAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/siteindex.gif R0lGODlhEwAaALMAAMzM/////zMAZohxxrau7GZmZszMzLu28ZmI1MfF+wAAAAAAAAAAAAAAAAAA AAAAACH5BAAAAAAALAAAAAATABoAQARiEMhJKxXGiME71tlGCEFQFCZ6pqVovXAMk+xqo4F4IF3v d4iDLCYoGo/I4iFBKzmfTxHtVsNJodjogDDser/g4WfjG4eCyfRx28xCr24sPK4d0d9stXqbOBD+ gIGCS2GFFREAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/spacer.gif R0lGODlhAQABAIAAAP///wAAACH5BAEAAAAALAAAAAABAAEAAAICRAEAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/nav_bullet.gif R0lGODlhCgAUAIABAGYAmf///yH5BAEAAAEALAAAAAAKABQAQAIPjI+py+2PAIC02iqv3qsAADs= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/nav_bullet_double.gif R0lGODlhCgAiALMBAGYAmQAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAACH5BAEAAAEALAAAAAAKACIAQAQWMMhJq7046827rwDwjWRpduGprmxbRgA7 ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/logo_cruk.gif R0lGODlhlAArALMAADBFl6uz1Wh3tO+y29rb6+zu9Zeiy+BpuX6Lvr7F31Zoq8oAiIqWxUBUoP// /8vQ5SH5BAAAAAAALAAAAACUACsAQAT/0MlJq7046827/2AojmRpbgGgBk5gsGcszzRnqPgzPbhq zApcIDUBMG4SBuBRCKoSvJxA0FpKeI5Cg9ozIHCNwg1XAMCU5d+38GiowkiHgSq5BanxG0HyVSEc BAZ7fQB/BAcDNYqLjB9ROY2RkpOUlZaXDk4ACpidnjEEPQB7inEToSkJcgBbDksGnDtmD3tTVToO PAVaXAgPOgYNAQV1S0wSUwp0AD9oDT8TN78IdK64r4UAxBehPaSAC+HhiZ/llwI4f2zEhNXm75Zj kPD09fb3n/IquPj9l49P/Amsgc5PlmPtaGg6U6gYtCVNcEDp4aDgpm2PGqjqQcsNq0A4/+iU0Sah x582b8QAqFPNijUkvCYQMiTIgRKDh8iRMCVBwZYGDVZlcvMAFgUe/KbokaXljytoEwqkcLFyQgoF QVgwQxDGwTMKeVpeK2pGQFcL3XB8IyBu3MC3HfS5zCUKKty7INKq+Ia3b1whLV74HexBUyzCiBMr XszYklTBjSM7SCCKn+TEekleZryuIo7DmxGn6AEjdF8XquQxmAzZtEDK3k6JUjXjF99jB3dgxP3r 10FaFXpvIyD8NzE2tk9tA/RrOfLjuAp8470rOi6Ao2RzlEFZlVkJboKu6rokRS0BSCfYonx9ZUxm 0cJIFUohgBsY8FMUMLvrWdgiY93QhOACyzE3SDoGOnCAOAeUwFMLQTXwxw0pIDXHUSF5psJqV4Cx B0X7qSCASj5kYYZ+rryhlV36iFUSWfdhIBdUA7S1QIMjdFdRGIV4MQoS3TxgXkXozTVFTB2uQgx8 EgwBiBk8mWVAMFwYkMaO/U1Z1YXgrcYDSCZyKAFxB+IE3ILh4FhCctKdQgAbO+zAm3AEkIIbnMwx 15yeEiDX3J1MHNPZc7llwRdx1vV5TGZrVeaaP7CppZ1Ej75mQGo4rJZAa5UONBoOdnXqT2cWgSYq PpkVeKpAn+6z6l2PlfbqrBREAAA7 ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/dotted_line2.gif R0lGODlhugECAJEAAP///8DAwP///wAAACH5BAEAAAIALAAAAAC6AQIAAAJARAKGmtfrmIwU2ofn 1bn27XFiSILmh46nmpbt6rJyTMP2i8+3nteZwAv6hLuhsYjsJYnKJvN5dEahy6m1uhIUAAA7 ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/__chars/alpha/black/bdit/base/glyph.gif R0lGODlhCAAFAID/AMDAwAAAACH5BAEAAAAALAAAAAAIAAUAQAIKBIIXuuj2FHuxAAA7 ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/__chars/mu/black/bdit/base/glyph.gif R0lGODlhCQAHAID/AMDAwAAAACH5BAEAAAAALAAAAAAJAAcAQAIPBBKGip33FnymQsaSuxYUADs= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/__chars/alpha/black/ital/base/glyph.gif R0lGODlhBwAHAIAAAAAAAP///yH5BAEAAAEALAAAAAAHAAcAAAIMTACWecfeoGLI2IsLADs= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/__chars/kappa/black/ital/base/glyph.gif R0lGODlhCgASAIABAAAAAP///yH5BAEAAAEALAAAAAAKABIAAAIWjI+py+0LgIlJSkVhuOjafnDP SJZOAQA7 ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/__chars/beta/black/ital/base/glyph.gif R0lGODlhCwAKAIAAAAAAAP///yH5BAEAAAEALAAAAAALAAoAAAIUjAN5C9eLHIxqvsjgNXfTmk2S WAAAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/__chars/mu/black/ital/base/glyph.gif R0lGODlhDAAMAIAAAMDAwAAAACH5BAEAAAAALAAAAAAMAAwAQAIWhI8ZELvJzoNUWjWr3nBm04AR 8nFIAQA7 ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/__chars/alpha/black/med/base/glyph.gif R0lGODlhBwAIAIAAAAAAAP///yH5BAEAAAEALAAAAAAHAAgAAAINjG8AGdvvFJtRtopOAQA7 ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/journal/v94/n3/thumbs/6602935f1th.jpg /9j/4AAQSkZJRgABAgAAZABkAAD/7AARRHVja3kAAQAEAAAAPAAA/+4ADkFkb2JlAGTAAAAAAf/b AIQABgQEBAUEBgUFBgkGBQYJCwgGBggLDAoKCwoKDBAMDAwMDAwQDA4PEA8ODBMTFBQTExwbGxsc Hx8fHx8fHx8fHwEHBwcNDA0YEBAYGhURFRofHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8f Hx8fHx8fHx8fHx8fHx8fHx8f/8AAEQgAlgBbAwERAAIRAQMRAf/EAIEAAAICAwEBAAAAAAAAAAAA AAQFAwcBAggABgEBAAAAAAAAAAAAAAAAAAAAABAAAgECBAMFBAkDAQUJAAAAAQIDEQQAIRIFMRMG QVEiFAdhMiMIcYFCUjMkNBUWkaGCYrHB0fFyomNEVISUJVUXEQEAAAAAAAAAAAAAAAAAAAAA/9oA DAMBAAIRAxEAPwDphbFdvsY7Gx0xwEuqmWV9YaQlvCx1sSSxPHABmx3clFG5kEMzKBIlTpoGH4WY H+/AaeV3MStOd28FBKU5sYQRscj+F7vZXAZaC/EjBtzUOKRMhmUUdzqGWjJiMh7MA12+aWSNg7xS iOicyJ9dWXJg2QocAHY9NWFlOJoXmJDatLvqFc+8V+134BnLPDFpEjBS1Qi9rECpCjiTQYBed6tr hDFbc0TyFooS0ToOZoZxm66fs4BJfXXVW22JvLydzb2lqHupVEDEuqnWwRI9RJPYo+gHAPI94ijs BNcLM0iR65USGR2JVakAImZ+jAYj35ZJYQLG8FvLDzvMtCyqpqtI2Q/FDENX3KZHADfzLZdOrVLT 9v8A3X8KT9NXT3e9X7PHAc//ADT+oHWnTfWW0Wexb5cbVbS7dz3hhI0tLz3XVmrZ6RgKotvVv1Ll lAf1AuIiJREHYOfAxGqTwwk6e09vswDOw9QuvLkRrL6mcgSu8DLKs4CxxqxVm02zDQxyUcc+GAn/ AJr6hyQ+YX1MhZzA10VeVkcNEQFQ6rcfENfCMBb3oT1b1Wds3pt232338rcW7RziRpljEsTMyjkR 11lh4gRgLt2rcvOrKHKc2JtLrHroAeFdapn9GABuJZn3+FHlUxxTpyo8qjVbSFq5cTxGAht7tZ7u 0A3QX2m6I0CNU0/BlyyHZgGF9a29zuti0pP5HmXSjUyrqK8pdaghWydiNXAivHASy7rFpcWiNeyq DRIaFagcDIaIP64CNLjfZHjpaQwxtGWfXKzMr5UUhVp2ntwEXmuoNP6aKvk+Z9r9XX8Pj7tMBS/z EWxm6p2wjZbHc6WVGlu4IpnWsr0VTJnSuAq1NqnB0v0jtAYKQ1LS2/E4gZf8sAXb9O7hM2mPpHZy zZRjy9qPGvv8TgDf4nf8nmjpHayhiM4Itrb8Faaj9VeHHAWj6PS3HTm37os+y2e1NPLC7JHyrMMn LYq50g68uGAtnatzW/SU0RXifSyJIstB2EleFe7AKXUydTkhfwrmKp7f0kmdP8sBJJfFJ4JLncLS SGK4d35Q06ESCVm1nW3ugVOABsvMbpL+bQyPvCR/uVokqyQ2lqiu0S1AVibjV4vpNOGA+tRFRQqA KqiiqBQADuwGcB7Ac8fMf1RvOz9XbZFYbXBfRvYB5JJVnZ1bnOAo5UsYp9WAqlvUzrJAAnSkbGoW giu/eOdPx8BofVXruoEfSMRqSoql0KleI/G7KYAGf1e9QEFX6ZsUUoXGoXfujj/4gYC9/l16x3bc Nj3i+37bLeyfnwJbJbN+Ipjc58+aTPsABGAuzbruG5jd0i5MgakkZMZbLIE8tm/vgMzWKPdQ3CBV ZH1yHSCzEIUHi7KBsAp6g2cT2/LWKGO1E0TOEZ4ncGqMrNGpNDqoR9pag5HAbW0T7TDdJZ2drbxw Rq7KjSioANOCHu7K4AqW/wBzjlljMcGqKLne9LmM68EPdgIm3TdGMSRLbB5YRcAsZiAmVcgg7K4A f+SXXL16LfT5XzVdU3DXo0/hfe/5YBR1F0L0X1zJBv11dTPHBE0CTQSKkemORi1daHMNXABRekXp /EIyt1KKN4GM0WbDPjozOA83pF6fmUqbqUSVNUE0INa92jAAXXoV6ZXBKy3U9VBJAuIQQAaH7Hfg Pq+jvTnpnpWzmtttR54Lh1lPmSktGUEArRVpxwDu2u9mFyYrZoVuZvEyoAGYgV8VBxp34A5mVVLM QFAqScgAMAOtzt94jwpNHOrgo6o4atRmMj3YAZ9i2qi6g4CNrX48wAYgf6/ZgPLsO1c7nhZDITq1 c+Y5k14a6YDY7FthJPLarLpY8ySpBOr73fgCvKxd7fh8r3m93+vH28cAHuEu2wGG3muRahyQI1dY wagmrA9mR+vALDF0pqRTcR1YtTxxUBTtP06RTARt/El1S85dQQTkgx6jU8OFdfs44DLzdLLMYjcV YMsWoMhUh/FWo+z3nswDbZbmxnSbyc7yxxPyirkEKU7V/wBJ7MASm3WCSiVLaJZQaiQIoYE+2lcA Ld7kfPxWVuUZ2do7hXBoCYWkQV9tM8ALbxXKXVnzbe0hHmGztSSf08nHwrgIN76d2hUv9xu7lLSK V0uLyd44AoEKFAWZkqQAeLk0wG9hbXVrbXUe0ETyzL8G4nTlwK4UhSdPjkFe7+uANW63+GZBcWcM 9qIayy20h5vOBGSxSKo0kV+3X2YCP+Rj/wCtv/0H7j+nP/tuP6j/ALvAcsfOVt11c+oGyPHaT3Ea 7UAWhjZwD5mU0JAOApe22va1Kc/Y91cCRS+kaax5agKwt4uNDgDrPb+lwI/M9P72aGTm8soKqa8r TW3NCMtX9sBtJtXSrW1E2bfY5/LAV5cbp5ntNOWp5f8AfAX78r1lcWe3dUfsUO4QwNdWZC3MMMcz Dky6gRIdGkHtGeA6K2qS+YSx3aS6kbwySCNQwPYvLJ4e3ALXkP8AJlUItPMqGcDP9IxzPeMBm0s+ Rd2R/a4bD8y9GjdXJrBJnko44DTet0tZb14HmX9v2tg28wtG7mRpY9UEKAZMakOwoewduAay3G6S xP5S2WFyp5b3TUGqmVUj1Gn0kYDATftYrNa6NHipFJXmez4nu4D2nfvv2v6Wnuyfq+/j+F7PewFQ +uadQydTbcm17ibKNbQGVAzLqJkkFfD3YD4+z6f62ITV1KSAShas2Yb7f+P9cAyt+mer5Aiv1Kqg gxsxM2WmpDmg+1gIb7pzqhVLjqYLVDJpDzZMhA0ZDi39MB9j6Xtv+2W25D9xG5vI8DseXcXBQFJD oCgqQajjwwFobRfXNyJluVpJG1BSKSIaSMvxPeP0YAQ2TQ76s7spFzPzIhnqAW25Z7KccAn3vcoN h25tzG3y20kUz8gTyGRZbiSGSOBKK0j/ABJWVBQduAY9L7DuEFpZ3e+zea3aOMMa0pFK6UmKkUDF 65mnDIZYD6LAewHsBzh8yvUDbb1nYQtul7YK21iSBLNUZXl58o+JqdKDIZiuAqv+Xxkvo6p3hVBj CaoI6kEjmE6Z8tI93v8AZgJB1UmsA9YbqEMjBj5YV5YUlWpz/eLZaf74CI9W0jBbqvdmcxMSogWg lFNC1M3untbs7sBdHy/dS3E1hvrWV5ebqBNapqvYSWR2SQkBYWkonDxE4C79rvZ7hZI7hdNxC1HI jkjQ14aeZx+rAG0B+rhgFm72Ebp5pnl1QukoCSOAoXwsVVQc9BPZgFst5ZfFWK8nMkpC2imWceIA Ag+A6Mz21wGrX9lJczwwXk51Rhbc82cfFzHahA48c8Bq13C7LquLgRpbpK2medaylhRahKlSe3+2 AI8ru+n3pNXkq08236jV36O7PV/2cBHuHTPSHUi2+4dR7FaS3oQxxrfxRSSogYnTVgcqmuWAXXfp 56U20PMHS+2T5gcuG1gZs+2hplgB/wCE+lPMZD0lZDRXx+SiKmhAyIGfHAFQenPpRNCsn8a2uPV9 iS2hVhnTMUwD7p/prpfY45hsG3Wm3x3DA3As40jDsgourQBUgHAbWW83NzMIn264t6mmuVaDtzqB Ts78A0wAVrusc7IrW89u0jFIxPHoqQpfLM9gOAjm6g2yGSaORpVa3kWKT4E1NbprAU6KP4e1ajAF Wd/a3is1uxZVNCSrLn/kBXAT4D2ArL1U9Zdh6H3a22y+2y4u7u6thcx3EKwsqpzChU8xlNfBgPiJ Pms6QE7MNivhE0elI+XanS9ffrzM/owEI+a7pQC3B2W+JiP5k8m1+Ll2fF8OA1f5r+lBFOv7NfiS Ri0D8m0pGnYpHN8X04C0vTH1Q6c6x6cG7WyHbdVw9qYboxRySSQqmpwsbMKHV34D7eKaGaMSQusk be66EMp+gjAKLya4l3q2iaMCGCdDG/a2uCXV29hAwEFnLE97ZBLu6uKXEgPmYylKQPwrGmAZ3Gx7 TcFzNaoxlcSSGlCzKCoLEUrkcANKbawFzabPHG+7yR60t3dtIJDCN5iNTJHqBzAz7KnAFWz7ybyl 1FbpackeOKR3czasxpZE8OntrgDcBzT8zttYP1ttMs+7wbdKu26VjljuXYrz5PEDDFKtM6ZmuAps WG0qyMnVFopjbXGRBf5MDUEfl+/AZuFtXMzSdYW5M9OeTDf+KgIFfy/ccBJJdyDkXB62hHLQxQOY dwNFNAVH5fh4RgOiPlt2Oyl9O2ki3cXiHc7qQz2yPGrseXqVhcxI/Fc6CmAuWxtGtYeUZ3nFSVaT SCB90aAowCOaj9T1Ffh3MAbur5WY/wC8YCS0u1nvLIDclviLiQUEapT4D5Zd2AO3i3ttyQ7TMNUE oD3lGZCIlNQNSlWBdhTjwrgBrfb3nkupLIRbfZ3KJGtzBGBdSadXj1mo0jX4Kg9p7cAfaTXizm0u I2fQgdbxRRHFaUbuftI4f7MAZgOXvmq2yW6632iRLmzhptmnRdXUFu5/MSGoWVlJHtwFLDY74aaX u0nSaiu4WZrn21kzGA8dl3IpMnmtmImpqJvbElafcJeq/VgJtw2zcriytY0m2TmwAqVW8sV1ClPE A9CfbgOj/lu6TnPpvEZ5LMyx7hdNriMd2ulmQ6Vkik0r2jvwF1bVZSWVoLd2jYKTo5SFFCnOlCz/ AO3ARzbcvn4rqJRraQNO2og0WNkWgGR97twCvdG3dZrSNNwsobgXJ0u8TEIhiatU5qeLTWmfGn1h i32HahJfve363X7g6PcAPytZRFQayr1bJchktOzAPfPWP/mIsv8AWv8AxwGyXdq7BEmRmPBVYE/0 BwEuA5n+Z3pPqTd+vNqvNu6YveoLNNpMLPaJMUjmNxIwq8QOYBrpOAp9fTfrwR2in0/3Vmhaty/K u6zDVXSRTweHw+H6cBhvTbr8rMB0Fuil6cpuTdHl5U7R4u/PASj056556P8A/n+6iMJpaMR3WbUA 1aitRmCae3AdH+gnSO+W3QSW+52Muz/n7uQ7fdpOkwjdhoodcZ00PEjPAW5t0N1BaJFctGzp4VMQ YLpGQ98s398ATgB7qxguAKqgbWjsxRWJ0MDTMezjgFV/tt2JbpILcSxXKh1kCwDQyCmgK48WrSM2 4YCKWzvpjck2TR+aVYdOm1blquRev2q6jkcAzi2vl3sdyJR4I+WyCKMajTjqA1DPOgwB+ACs5ri2 tUXdrmA3LM/jT4aldXhADHsWlcBrd71ZW8YdGFwSwXRE6Eiv2jVhkMBB/JbLW6mOUaK+LwUahp4a PnXjgC4d2sJYlkMyRlhXQ7oGHsIqcARDcQTAmGRJAuRKMGp/TAARS78bxFkhiFpqId6+PTnQjxfR gD5ZVSi1XmsDyoywUsQK0GAEt769aREu7Py3NcpGRIslaIz1NKfdwAN51XaWs11E8EhNrKkTNzLc BjIheorLqAFKeML7MAftm7QbgshiUoYiAwYqTn/0lqfXgJ/OWnnPJc5POcvneX1DmcvVp16eOnVl XATYCo/WP15svTzf7HaZ9ml3CS6tlvBcRyxxgKZWRo6Oj+9y+IwHwY+cTbTPI/8AG7kRsmlYfMQU Rvv15dT9BywGF+b6w0W4/YLktGaytz7f4w7iOV4f8cB4/N3ZFZ1GxXStI2qJ+dbfCH3QOV4vrzwF uemnqpsvV3TUW8PCdtlklkg5MrB3fkUBkLRqq5k8MB91BPDcQrNCweJxVWHAjAJZmln35IpnVoo5 XSFAQGCva1YGmdanAaWMMUd3a6LK5tqztU3EmsH4EnD4j4BxeyWEFtJcXpijt4hzJJZdIRQPtEtk KYBb5S/vWu44XXbtrniWOGW3TReFjrDyBj4UFCujw6uJ7sAZZRbXbTm1hdXvVjDSlmDzsgNNUjHx HPvwB2A5T+bMbWOv9oa6vmtZTtSqqC1FwCvmZTXUXShr7MBTtrc7LDHAibuaWziWMtt0ZOpSSNRa QlhnwOWAZp1FZhrxhu6k7jGIp/8A4q3zVVKDR4vAaNxShwBEXVVnHLYSjcYGO2xtDAH2e2ZSrqEP MBakhovF6ntwHR3y+ptN70L5uTcDrm3O7nCxgWKFndWIECNp0g8KZezAW7YQRQ2+mKZ7hCSRJI/M PdTUcAjiUydTu4XKK6YE/wDowK0/ywEtly/OWwR75yLhgTdhwv4Enu6gMsBjdtwW8e6sVsWu4rV4 0e3kXTHdTOodY0ZgVZYx4pD2Up34A9tpkuTKb+5kljmQIbaJmiiXjqpoIc1r2nAF29laWyqsEKRh V0jSADTurgJsByl82ttDJ19tDvuNvZt+1KvLmExYjzMpqOXFKtPrwFPWKR20kEkO92Qe2cSQ/DuG 0sO2jW5r9eAZHdLlkvkbfLAruIAu/gSeIBdGR8r4PD92mAn/AJDuAubO5G+7fzrCNobYm2egRgAQ y+Vo2SjNgTgOjPl72hdx6A85JewzyvuN3JJNDCpVi7q7D40SFfoUAYC39tsmsrUW5kEgUkqQiRgA 9gVAFwGJLBDfRXSBFKszynTVmJTQCG7KDAJN1k3CzMQgvWurtbhRpnXRHGsqMmrVHFIagN4R2tQH ATbfe20E0r3UiLHbKEgWNZmKBhqkaQsg8bt2/wDHAM23rbl16pGGhdT1jkyXPM+HhkcBvDullNMs MbkyMNSqUcZd+YGAKwHK3zUTrD6k7Uxt7G51bMoCbgQEX81L4k1NGNX14Cmobh/2zbo/K7OVimDC UmHzEhq3hufHr5ffrAFKZ4AkXb69yrZbLWWNQRqhpF4CK2tJM27To1eLAeF6BNtrHb9lbkxMNBZN E1UA1XVJRRxxGoqa4Do35fYrGb07WW8ntrWH9yvCbZY9cdCwIEbFskGY7fpwF27TG8djGpmjnSnw niTlpop4QFq2ALwEV0IzEOYXC60oU1VrrGn3c6V44BNuKXPO3HlO3KZI+YK3QYNlTRy1IpTjor7c BG4vTJceY1LqiUXZie7IWLvhHLzkpx051wDCJLPztsVkujKIgI1bncsrp4yVGjV/1Z1wDLAf/9k= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/journal/v94/n3/thumbs/6602935f2ath.jpg /9j/4AAQSkZJRgABAgAAZABkAAD/7AARRHVja3kAAQAEAAAAPAAA/+4ADkFkb2JlAGTAAAAAAf/b AIQABgQEBAUEBgUFBgkGBQYJCwgGBggLDAoKCwoKDBAMDAwMDAwQDA4PEA8ODBMTFBQTExwbGxsc Hx8fHx8fHx8fHwEHBwcNDA0YEBAYGhURFRofHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8f Hx8fHx8fHx8fHx8fHx8fHx8f/8AAEQgAlgBcAwERAAIRAQMRAf/EAHwAAAICAwEBAAAAAAAAAAAA AAQFAwYBAgcACAEBAAAAAAAAAAAAAAAAAAAAABAAAgECBQIEBAQEBQIHAQAAAQIDEQQAIRITBTEG QVEiFGEyFQdxgaEjkUJSJLFiMzQW8OFyksJDU3MnCBEBAAAAAAAAAAAAAAAAAAAAAP/aAAwDAQAC EQMRAD8A+lTEvFWC2dkkukVMczssgVpHrRmlkUnUzZCuAG973ArprEYVGAmG0gJ1EBQK3ORPhgNI r/n94bhiZC+3trGgOoCpUH3PzUHTAYTk+XcgLJG5df2wqxZsh/cI/fNQP0wDiwvlvItxUISgpJVG R+oOlkZxkR54AIds8ct7JeBpBLI5kddQK1LBiKEHI0wDC8u4rSBp5QSilQdIqaswUZficAnflDHd zqvKpM8ZA9mYlUrWRVzYUJ60wE3L9wHjrow+33FFu05lMioKq6qEoQTnqrX4YDPEdwpyM+ztLE+j coJA5yNOlAcA3wAv1Sy9r7rcGxubOuopq3NrrWnzYADlZLv34iitJLyPbjZkSVYgh1t6iGZa9P0w AjXHLtu14Sc6Z1RNV5F+5GCaTD1mlKD0n1YAY3PcVCV7cfUJn015CMEgKdM2Vc2+XzwCmXku9ojG 0fZbatDsxXlbcFHJPorQfP4keeAN4jlu5UsFefi/o85ah49m+oAICxDqbcqq6jgLHxvKTTSm3uY3 E1SVYQyxx6R/mfKuAB7mMIuIzIzCkBooAK/7iHPMjMHAb8hdTb91Eb61ZAUpagfvLV0+Y6/Gvl4j APsB7IZ/rgK9e81HeyWMdncqLe9d47daEG6ZULMqnqscYUs7eNKDAG/8ftvo30rem2te7u7ja9e7 vUrX5NeWj5dPpppywCfut2XkkIWVwsC0SE+qpds+q+WAr/1CN7q4tokupJ7bRuorioEgqpzkHh54 DF1d3cMkaRWd5cq8mh3iljAQf1trlU6fwz+GABh5fmJXRX4TkYFbXqkknt6LoHpqFnY+vwp+dMAz 7U7h5lbW5uJOPm4+TWiNb339w5UaqOntGnyJ8zgLpxfMNczvb3ACz1JjCJKFKgVzaRVFcAD3Iu5e RpVcrc6q1JFbiGnQEgGhwE/IJcGe5otntkx0Ir7j50+bL+H5YDW4704SGETn3L2x1AXCWtw0etZR Do1BPmLnL4Z9MBrx11f8tY2t3cWrlJ4o5fbvWCIalDfuB/3WPwKU+GAYcTa3ghW45JYhyDCjrDUx RqDkkZahpTr5n8sAfgKb3zyScdcR3B4LkueYoka2/FKryR1Lku+qSH0+mnXAVWTumTdmiH217kdE YLrpbgOpyqK3IwGR3PLHVV+2ncgRGK+k2vTzA91gIv8Al9yaf/mXc1M9X+2yPhT+5zwFk7X7hma0 luo+37zgZXkEL2XLVWRtIJWSMwm4BX1U8MBb+O5W1vgVjesyKDKgDgAnLIuq1GAIurZLiIxsStSD qU0ORBpXyNM8Ar5vi1kguZLa2iS4liYveVVJVZSpUqSkgqKVFRSoGABs+OuB7KK4eS92oVmiM13Q HaZGV2SKKNSRl4UwDKLl7uT2tLeGl3GZIjvk5BQ1Mo88j4YCMc5dyRW7RW8Be6LrApuCAWSoIrt+ Y8MBn6+fae502+je9vXf9O5q001aPzwE1pPxPL2y36RkoS0QaVGjb0OUIo1DTUMsAR9M4/psrX88 B76Zx1abK18sBj6fxlabaV8q/wDfATQWltAWMMYQtTUR406f44AS+5zj7KQxzswcUyCk5EVrlgGA IIqOhwGGVWUq2asCCPgcAubgbRk0b10q1BAW4mFKVAp6suuA8/AWjzbpmug3gBcSgD4ABssBs3B2 bSbhefX6895/5+uVf4YAn2UXtPa6n26U1ajr/wDP81fjgBOYNuwEM0zaHCh7ZRGaguBrOtWyXr+W AUtx3b8boyyEyROBDQQVoSCzLVOikkn8MBHHx/AQyKyBkfd2w1IK6af6nyfL+uA0SLhCVWQSQrIt Ji3tgE2zSMNRfGnppgH3DXfuYS5lkLkCsE21rjzIGcQA9VMAe0UbGrICfMgYAfkOQis4gxo7koBF qCmjuqVz8AWGAUXLCKe7kjXkElWpDuW2PnX5M6f9sAXy8XPNPr46XTELeRRH+3QzFl0N60Y5AHxp 8MBpxC9xrcAcidcOg1asfzVy+VVPTAOcAD9Wi9l7zak2d3b+U107m3u/+Cnrr/TngFXc0t2txt2n Jvxczxod6O3S5LKDJVdLggdRngEEkfOuZ9Hds8QYj24XjLb9tfFQSraq/HAANxPciikXe92o1M40 8ZZihNRSm0a9a1rXAL/+Pd5VFPuHfoFUoK8ZZsDXMMQY+uAsfb3C84bOSCbnJudvEcSSX849g1H1 UTRbAVApXAWvjLflbeUxzCNrZiW3DNJJID4AB1Ap+HTAAdxvCl+jMjF9lKMGpl7uEdKHoaGuAzyU ke/fJ7m8LhRWAodhc0+VtH/q88BYcBpLNDCheV1jQdWYgD+JwCG/5wXMlla240JfSSRrHKGjknCI zFYxSqp6Ks7U9Py1JGAN+kXf0z2v1CXf3t/3FF6b27s6aU2aft6eujxrngB+Y5K1s+QpPee0aSJC p0htQVnrkQfPACy9xcU6gJy+0wYNqVAaqP5fUhyP8cAJJzFuzBl7ldAJtwqIISDGf/ZNY60/zV1Y AJ766MaqO8W1Dc1ObK3qdQonRQBoOfx8cBNxdjyF/bvEnL/V7mAqXu5QbTJi1EKWojrTqMBZOLsu TtJ3WUxvbSEsTuSvIDTKmvID4YATnYJZb9TRtpYY9RC1XV7mNhmSB/JmK1wHuUu0M93AORYsFUey 2hRSWT+fTU1r5+OAj5Pu21eaKx4hpLu6lY7k1rEbhIkinWGXVQhdQZitK5UJPTATcRZyTWltNFDL agxqRLffuXoFOhVtSxn/AKpgGPG8VbWEIjRpJnqzNcXDmWZixJ9UjZ0FaAeAyGAMwFK754rmr3kb duOnntQka7ksMCXGsBmrGdasF6g1GeArK9qd21kJ5XkBruN5dNnB6Y8/2M4m9OYz+bLAeHafdQJP 1XkjWfeANpAQI8/2f9H5c+vzfHAZg7Z7ziZSeUuplExkdZLCPOI0/ZBUJSn9XXAOu1e3+6US8XkL ozSPKrRTbcthpiow26Iz6yK9cBc+OXlEBjvBDtqoEbRu7saf1Fx+uAJnt4Z0CSrqUMGAzGamoOXk cANy9rPc2ksSSBInidZE0ay1aUpRl8Kj88At4axHG2VraWMsUNltlh+2zaTVdKl2kJ/moKmuWAIj u+SJsw8yIblCXBgIKNpBAIMnp8euAi9/ybrDHvrFNOzpVrc+jTUBiDL0OVPPAY9/y30/3G4a7u1/ tWrp1U3NO50pnXpgG1hNdzWqSXcHtpzXXCGD6aEgeoZHLASvJGgq7BQcgSQP8cBkMp6EYDIIIqMx gPYBXdcryUN68Kce0kCgFLhWYhqrXoqGnqywDQGoBOADHM8WZ3t/cpvR11oTQihAzr8TgBbqx7Wi kMV1DZxySKZTHII1LKhoXoeoUv18K4DMfG9sXUmqO3tJ3Kg1URsdIGkdK5ZUwBX0jitQb2kWoEkM EAIJFD+gpgJPYWXtfabCe2/+HSNHWvT8cAFy/K2NlNGtxyAtnbTSENEGKs1Nw7gJoPhgFVxzXbd1 cG3uuTWSKECWOaR7UoX8l9NdQwAA5Pszajm9xGsly+iaPVZh0BYktJQU01zNCcAdF3P27A72sXLq kFvGDE4ktBG2XyJlWo+OAadv8xZ8pDJLb3ZuNBAeJmhZo+tCdnL1UyrgG2AV85yjWkezCSty6GVH oCAqSIrVr/8AZgBORuZw17C19aEKp/twtJgCVoG9fkfLAT85bcTPPHHcyOL2aGSO3giYbrpqQuUQ 16HTUnIeOAB4fieds5bSfYgjLRst9C1y0mknNdDC3TXn1LYBpbL3FK1u901rbKkrm5ghDz7kVHWM LI21oOaMfSehHxwDLAc4+48Vyeftnjm2kFqoZaIdR3H/AKjUUwFCueO5x7q5dOVYQyq4t4Nq3pCW HpYMTqbT/m64BZJwXcjWscY5uUTqzF5xDaVZSAFUqaqNNDmPPAavwHcLXdxKvKSiCRGWK30WpWNi tAwb5iVPqocBePtZ27zp4/kYrq9N5OJonWaVhb0XQ66aWhWtDnngOncZacpaymOUxNasSxOuV5K+ Hz1FMAD3TLMjqI2ArbyGhp13oQOv44CXlBcB7wkWYjKekivuP5fm/wCvLAbNHPedxStFKIoLKAQS OqKZTJMRIVSRgdI0qpYUzy8sATHwojEIjvbsbII9UxfXUUq+vVWmA3gsb6MwmTkJJtt2aQMkQDqQ 2lTpUEaajMeWAOwFC78oOYjJcJqtkANUrlJJXJiPPAUm6s797ySaLkxHAyMqW+i3OlitA+stqNG9 VPywAH0zmxbRp9dG+sjM0+1a+pDSiadVBShz+OAJNrfblwy8sqJKpECabc7TEghq6/VQZZ4C2dlc Zyc/HzRw3a3V1CyGWdZTbBtRciq25foDgLzxdryttM6T6HtnJbWZpJHBoKABlAA/PLARc/ZPIwuj p244WiAozMWkljPQUy9HWuWAi5e3dTe3LWFvtCPUboZzsF0k+kISaUyz8BgDO3o2+mrcyKyzX7td yK6srDeOpEZWAYFI9KUI8MAywHsB7AUnvjgea5Hko5uMmjgZYURmmt5Z1b1SGg2ilCKjqcBW7jtD u0yylJYTEVIhHtLjUHoKFjqoRXwoMAum7L74McYDQmQFt1vZ3Gkio0hRrypn54CF+ye9tc5VYyjV 9sPaz1X1Cms6vV6csqYC1dj9tdx21rcx3Y2bh2iLyIZ7VGUbgIUepjQMOpwF749eUQGO8WLQigRv G7uxp/UXA/jgDMAPeWNtdoRNGshCsq6xUDVSuX5DAKbjjFtZLRhai4QR7Uqxxsx1mn7hq+S5fE4A O3gVTbbllIRbBxcf20g3a5Jo/cby8a4Ay04OY29m9IVkRzLNqicEqxrpoXNCAT1r+mAfYAG2lezi KcnfRSTO7tGzBYv2y3pWlc9IyrgNbvnLGBUMbrcFmCkRyR1UH+Y1YZYAcd0WVXBikGmtDWEhs6DT STx64AyHmOOkiSQ3EcZYAmN5EDCvgaE54AiG6tp67EqS6fm0MGpXzpgAeQt+cklY2VykMRpQNQmt Pijf44A6WeKCIPO4RahSxyGpjQfxOAEPMRLNJHJb3EaxfNM0REfUDJvHrgIeW5+PjrjaeBpALeS4 Lq8a02yBp0swepr1pTLAacR3NbclOsKRNG7IXGpkOQJB+UnywDfcjy9Q9RoufUitQP4YDOApffff kfbl7bWptN154xLv7ioQFfNKMj11UwFUk++llHfMzWSqqRnVaG5jAFPUZCdrV8v6YBe33+4xbOEE oC0pK3Xubf1hfUYv9LT0I6Z4Dd//AOgeKW7vA0SKUj9dt7qH+300Bk/0tXUj5ssBbPt/9zeP7gsJ 5xFJKsLKguoaXO5q1nPYRQoTTTAXq0u4rpC8QcKDpOtGQ1HlqAr+OAT9wSP7pIzOFh242MJrmwuo gGNB08MBFfyxiW+i97du6gVgaM7S1ZT6X28+tPmwD+5njggeWTNEFSOpPkAPMnIYCs8fZ8xzA43k rm4SMJEzSGAzRxOZVUVSMNGXXLJpfyUYA3j+z+Os3spAS0ljLLPBRI0UPMrqxoq16SnxwD3Act+7 XH2l3zNkZ3KlbYgCikGrnz8cBze84HtgSTNcSR7ojbeLCLVt6PVqr4aP0wFclsvtWONErXNkbBZW Cmtvt7pQFgD01FQPywGJYPtk1/eQyTW5vHgaS8FIi7QiMTMXoOmkA4Dpv2T/AODnheRHFq91xoni RY7WNyqyaZGb0xBT0PjgOucVb8Q9xJc2kMscsfpcybqg6h4K50n8RgAe4ozJyMaBa1hQ1rTpdwmg +OWA35O7G9ewnk9RVV/stpRoqU/npnWv64CXlFuLvlre2SYC1VGWaAD1NI+kh9VctuMNlT5nU+GA dRxxxoscahEQAKiigAHQADAZwHsByr7u3yWvNWIKM5a2JypTKQ+ZwFAl5iA1rCxrkclPh+OAH99Y lCvtvQeq6Y6dPKuAyl9YoxZbajN8xCoCcqeflgOgfbOfgrq15ReRXbgDwABzpUtplP8AIfJcB0yy 4ziVkS9tE9TLVJA7kFSKdCadMBJfcfHc+pQqzHQpkKhqojh9OfxGAX83JeQRXbyXcWw0ZaG0KBZD pK1AdnUZ1pn54DHDG0onI30kKcnOrM8e6jbKykMYlYEg6aKCw608qYBp9R480pdRZ9P3Fz/XAZHI WBIAuYiWNFo65n4Z4CfAcf8Avpw3Z3IX3GNz/cN/wsiROIU4+2vLhnUtmXNor0A/zYCgSdrfa038 zHvblQ5hYMg4/ktkLs0JT0aNenMUNdXxwAUvaf2l+moj9881tbzESDjuW3tWlcjSPXo6UypXAGN2 p9rzyc7jvjlVlaFg0Y4/kdkAxU1J6CmsDMUNdXxwHQ/tDwvaPH8ZyacZ3DyXNRSTwtNJPbXdvLGw VtC+tFZkP4UrgOl8XHZrPKYJbpyR6luBNoBr/LugCv4YBlgI5hEVIchSVahyqB40rgFUyyRz2Bs2 M4EJQrVEG36ayfIanpkKYAK0e9X2JELtso/txuw0mVv6qIukKKdKYAu0tYjbWH97KHWRmHpjJZzU sholMvUKimVcA7wH/9k= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/__chars/greater/special/ges/black/med/base/glyph.gif R0lGODlhDAASAJH/AMDAwGZmZjMzMwAAACH5BAEAAAAALAAAAAAMABIAQAIdhI84I+n/woLUyPGm WaH6zHzb0CVLA5TIJbbu+xQAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/journal/v94/n3/thumbs/6602935f3ath.jpg /9j/4AAQSkZJRgABAgAAZABkAAD/7AARRHVja3kAAQAEAAAAPAAA/+4ADkFkb2JlAGTAAAAAAf/b AIQABgQEBAUEBgUFBgkGBQYJCwgGBggLDAoKCwoKDBAMDAwMDAwQDA4PEA8ODBMTFBQTExwbGxsc Hx8fHx8fHx8fHwEHBwcNDA0YEBAYGhURFRofHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8f Hx8fHx8fHx8fHx8fHx8fHx8f/8AAEQgAlgBiAwERAAIRAQMRAf/EAHsAAAICAwEBAAAAAAAAAAAA AAMEAAUCBgcBCAEBAAAAAAAAAAAAAAAAAAAAABAAAgECBAQDBgMGBQUBAAAAAQIDEQQAIRIFMSIT BkEyFFFhQiMVB3GBUqFicjNTJLHhNBYIgpJUJRcYEQEAAAAAAAAAAAAAAAAAAAAA/9oADAMBAAIR AxEAPwD6Ntp4trlktrW2lnt5p3mefq66PK2qQ0kIIGok0H5YD0dw3fRZztkokDALH1IqkEE1rq8K Z4DOLfrllq+3yRsCooXQjM0JqD4DPADHcd2VVhtU41Z0Z4gQPeNWWAfsdya5mkjeBodIBQsQdY8a U9hwHu67d9QthB15LejB+pC2lsvA+41wCemPZbWUtcmaZo3MCy1zMStIRl+ZOAXrHNuNtPJBf9WQ RuXhLelBKA583D24A3qN3Pa6zbeC+4mIdHrKJTqr8amWHVTx+ZgAS7l3OlzKFs9UC6dBEQJOSluE x9p/zwFte7rZ2IgFyxWS4bRDEqlmZgpY0C1yAGZOQwGstfd4z2G63UKyQJLIW2sGGKWSOHpJpOjq JrqdTZmudPDAbjngOK3v3n3SG4uSu3iR2XpvpVtJCkgBKzCh5znlgK9/v13EsyuuzAlYiFJrTPPS R16aqqBX9uABB99e4VeyUbIAsIYIzMToFCvzP7jny4ccBgv3u3tVtx9Bmo1wZSquSUbl5mPqc0z8 vu4YDaexvuhuO8bjuUf042ThGuHe86gjcrIqVjKyT0WjcAo8MBvVl3QpdPXS20cbjJozKSW1FeDI Mq+3AE7neJWtS8es6LrQa0IPpnqKDjUYAaTweo2xfVXkTNBCVt4lLQEEGmtghz9ufswFjsJA2a1N TTQM3yPHxrTPAVEfdF5uG6PBswt7i2VJIwJTIkhmhmMUkmS06ClSur4m8teOAYk2XeZXg6txbssk obc36bl5YQrfKjq1I11lf+mvia4C/wABMB83XUncfWm/98Fq7UPr4zTm982AD6nfVYau4hSmY+oR DP2/zcAGebuF3rH3P0xpICjcIDU582cuAREfemqEjvAkISZQb225xUZZS/4YDcPtevdMW5Xo3DuB twrbMY9F3AWU9WICg1yL7tRGWA6pts+9AxThLi8ioyyRG4tpFBrTNkpVgDngG+5VZ5rSNSRqS6Lq ASxX07LkPHNhgPPVLDPt1udz9MTDEPRiIN1MqeZlqtafswFdFJZ7rtv0S9DLtiW8Ml9eO3RjmEzM VhR1KEHkDPSlAQPiyC+2wQzT3V5HpMZYW8DLSnTgqCBTw6hfAWGAmAmA5Lcf8eNjnadn3GU+oYvI ChOerV/U9vswC7/8a+3mYsdwepj6R+SPJTTTz+wYDBf+M3bytGy7lIDCCsfyVyBJJ+P944Dxf+M3 bqrGo3OUCJi6ARAUY0/f/dGA2LtL7N7d23f3N5bbhJM91E0LrJGGUanVywV2kX4fZgNwtNmubWVD HfMIAQXtxFEqtQZ+VRx9uAsbiFZ4JIWJCyKVYqaEAimRwA3glWKKO3dU6ZUEuuqqLxGWnPAavZ9s W1lb7jLFbWks0kxaeSWzklaZsm1EGRq5n4MsBcW1vfWk3obZoYrdUaYBLaQLqZyWAPV01JNaYDBb 3eDBayNIlZ5OlIBaS1XiK06lVGrxbwwA573ewLqVJ1CWZIKCymbq1FBppJVqNWujwwDXqtw/qj+R 1/8ASycP0/zPP+7xwDG13t3dwSSXVm9k6TSRpHIwYsiNRZBp8HGeAcwEwEwEwAbu4NvbtMI2lK0+ WlNRqQMq4ANhuPqopJHgktljND1gFqKVrxwGEm6Ot2sC2c8sTU/ukCtFQita1rT8sAjc2XakG2tf XTLbbfKql5ZZpIY9LMCoIZlC1NMvywAnt+zpZBbvKGeGkYQzzZGpIHmzNTgLCTt7a3jEZSQKBSom lBpqDkatVcyM8BE7c2hJOosTh8wD1ZTxFOBamA8/21s/9FvZ/Mk4fp83DAKTW23y3M9w8pE8ZB1R v0xIdPwgSAGnDmwAW2nZlRrYTuYlHVqs7UZsxpB6ta+NOGAkFjtSrDGksiLKvUJaUkRMlNKvWQ0b nyp7MAtHYbSUgB9VVmKHXOSygGmuQibyn3YC32RYBNdmHWvOQ4kIOsjhIlHflNcBbYCp7hkuxCkE IBhnjuFuCaZAQMV4/vUwCadKK6sFaXcEdoomEcQY2w5dNGopX4cxgHrC0gvNgtIJi7RPDGSVZomN ACDVChGA9btzajK8uiQSSNqZhNLmf+7APXF3bWwVriVYlc6VZzQEgFqVPuU4Crbc92v0mTarU2xh mRBd36FY5EBRnaFFOtgyMyqx083twFzgPmG63XZNLRHcmXSaalioRQ/jgKq43DtzVIzb3NGCukgR 0C5Aah78AD13bLFD/uO4AVCvkFGBDc5y4ivH3YDG3bYD6YR91XT9Ji+axkyio5XyzA0+GA6B9qrf bIk3knen3JHSBtV4SiR/NNFDQBWz9mA6lsjSLcqthNZyuY1MyCS4Y6NQzUOWAypT24BvurTqtamh KXYFOJ/tnyGAxSdIZNsibcpbdmghparHqjfLiX0mlf4sAzButltnbEG4XstLaGCNpJVUsTUACiqC TUngMBhZTb/uNzJO1dt21dcMcEkQ9U7xysvWDMWVI3QAqpSvjlgMp4u2re8tnvZIpb+JybWS5cSS pJoYEx6q6DoLDlAywB37j2ZUd1uOqsbCOTpK8mliQKHQDTzDAWWA+UrmKJmnc9oa2D5LqkGupNWW t0KAfvUOAFNYWgMg/wBoK+lQykPLzk05R/deFfH2YAPoLTUgPZiUZCWYvKdJoeQ/3Xj7ss8BjFYW fySeyY4yzENUyHpivmNLnx92A6F9poUhXfFttoXYaRQnrIZFL0lpkQ9zTLhy1r7sB03amtnkgim3 OdbyoCIjOyuDz8xeJc2HmwF1vFi06rOpYm3jm0xooLs0kZQaSTkRX2YAbLewiyf1qWtsFjjeB4gS z04aqppr+GA1fat1u9c12yK09vBFDYxXF5AtnRNQM6Khdlkk1HUGzC6RlnUL63ttmWQvebub6Vgd aTXKiLmctlEpVABXSPdgHo7vt5BH0p7RAp1RaHjABKkVFD+knAe/V9hjcp622V5SWK9VMyKAnj+G AZ+oWH/kxeXX518v6uPDAHwEwEwEwEwEwEwGE+oRMyRiV1BZIyaVYcBU1pgKOWW/NvcL9MuGeeXU QPSkqtBwq2lvL8WeAJLdbgt88ibZcMrRrESptwBSragS2o01UocsAE+vhSxjFncubZhQqttzAqaq 3NRFUctVOAGybnLb3cXo7mKSV+pHMVtCRzA6VFWrw4tgLvrS/wBCT+R1OC+b9H8X7MB7YWCWULxJ JJKHkeUtK2pquakVoMh4YBRu59hWuq7VSp0sCGyPsOWAIe4dmDohulDyadAIYV1mi+HjTAMWu4WV 2zrbTLKY6a9Phq4f4YBjAK7lZS3luIormS0YMG6kRoxAryn3HAChhfbraaae4kuVjjLHVUtRNTGl TxNcBXy3m3ybnCx3C7hlk0OtoA3T5lBAPIy8OOeAzmn3i57Z6u2TM24OKQzhImYgORq0yGNPKPdg AiXu4XDkx6odfIKQ101/jwFzd7nt9msL3VxHCs79OFnYAM2ktQH+FTgMNu3Nb5rnRBNFHbyiJJJo 2jWUGNX6kWqhZOfTX2g4BzAaJ/8AS+yRISJnNvoGgmCcvrqakmnClMAvF91ezFt29RchZ68hSC40 cBxqK8a4DyT7tdiC6QJdf2+WsNBcdTx8tBT9P7cAP/7B9uxHKfWqulgIiIJ6BMsny41rgL7tvvzt TdNulvrW7XRA0cVzIElVOo4JUKHFTwOA2Cz3Tb71itrOsrKAzBa5A0IOf44Cs7nEJNt1HZQEujpA qGHp3BrmOGAJBJfD0Cw3lvHbGCLVBIvzXNOK0YccvDAN7IX+lxGQgvV9RXIV1tWlScsAqi7luO4N PHd9HZOl00ijWkssoaplEteWPTyigqeNaUqEt9k7V2a3tI0trW1itmpZvLp1I+k+R5Ktq0lvGtK4 Cws9wsb3q+knScQv05Sh1ANQNSo9zDAMYD5dMPbbtKn0yX54IlJnqGDLQgt0KGoywFdJsHYotOgd hc25kD9ESVGuhAbT0PAeOAE+29ipe25OxXHqEVBBMGYiMLkg1i2oun9mATTb/twsVzGvb9wkRoZ1 o4D6WyoPS89Dnl+OA6z9nzssHa+5jZbK4s7ZbiAGMTLCwyfP50cIQV45Z4Dom2GOa5iVrm6twqq6 FrmF1k5s1otSa1z/AGYBnuhSz2igA6luhqY0UH0zgE1/HAZpac+3sNqjudEESm8dow8dBwoQWNPc fHALNY225bBb7JPFS3vdYuYUYrpgjkJdQ0ZUip0pkfHAXl5dC1hUImuVyI7eEZanIyHuAAqT4DAJ WGynp20+6OLvdIud7j4Q+kqRGtAFXm9n454C0VEUsVUAsasQOJpSp/IYD3AfPEey/dPrXPV2a3MI EhtCLZhIWp8vq/J0gE+bT+WAGdm+7XpQfodq12ZM1Fu4jEen2mAtq1e6lMBnHs33SN7Er7FCLLTH 13EBMgYj5gQenoQD5a4AH0j7u+nuSe37czinpFWFtLc9D1CbfLkzy8cBv/YVj3NDsN+u87aLe5ea Erbi1WVGADaqKVg1ZcSeGA3DbIrUyQ291thM6GqXRtEijGjmFKFtNPDAW99YpcxkgL6hUkSGRhqC 9RaGo8QcApPt8Eb2k8slxriEcKxwM/TJFc2RKCn5YDX7K43eC2vpBMtu6OYrV3srqV44VOsCUnIu WdmJA8R7MBb272MW5+pkkvri86JSkkMukIWqSqLGqqSRTLAOrvtk6RuqXBWb+UfTz82Rb9HsGAPa 7jb3UkkcayhojR+pFJGAaA0q6qODDAM4DxWVhVSCK0qM8xgPcBMBMBMBMBMBMBW7lt91JC4sivUl lWWQSySKOUAUUpUjyjLAAS138DpsLXpLEYUYST6qUoK1HtpnxwGENhvcUCpoty8cgljPWnIrpIOo kVIz8uAtLWzWJ2mNRNKB1QGYpqqWOkH3scAxgE9vsdt26KSG0CxJJI80g1E1dzVjzE4AE+/W8M0k Rt7lzH8ccTOrfwsOOAxPcVqI1kNtdUauXQcsKU4gZ51ywDEG7201x0FSVWoSXdCqCnhqOVcA2JIy aBgSfCowA7u1iurdoJa6GpXSaHI1FD+WATS3s9ltJ3jYtUNLokcVYolSFr7lwCL/AE2fcoLmSyvP UyiNxLH1DCKrUVKsFy8csBm8F/f9rSQWc0sF1KrpFN1DFKnOQPmMkxDAe1TgAtt/cwnkdZWZDTQv qfYBXjCKeP8AlgNhZ1RauwUeJJoK/ngEdu3C8u726Pp1Xa0WL0V3qq0zHV1eTwRaLpb4qnwwFhgO WL93LYG4nGzs0cceowajQaAWYqehmzVwFWn3y2+12w3Uu1XdzHI8caHQ/VUyLRaILcGnLUnwOABv H3/2i1s7OaXa7u2W4DshjileQhOU9RRbnTnmK4A3/wCg9hPcCbX9KmW60hRCVk6TGRVkVup6elQu XHAZdh/fvt7uvfZbDb9vuJJQrSdFxQqIyz1j1xRg+AoWHDAdTs97FxIqPbSW4avPI0ekEVNKqxqc vDAK9z+nratKGNEuihUjT/pnqD+XDASCZ1axUbukCPFEyWTrGXZSgHEnVmRgHtiNdriOsS1MnzFp RvmNmKZZ4DC83eWPc02y1tZJ7mSFp2npS3iAZVAlk8GbUSqgVND7MAovbElzZx2+9bjPuPTuPU0W lvGSk3WjRlj5mRMl0sxDAZ4C0t9xsLi5ntbeZZJrXT10XPRrrpBPD4TgGcBwOHc4WYR+jjVQPNQh MhXL5v5DADud2aK0M0W1rPKGUC3VlViGOZq0wXl8c8AhuPcl/bw20kHbnrHm1daNJYlMWk0GrVOA dQzFMA0+7TDcltl2ZGt2FWvtaaBy6qaetr48vDAMdibtdXu60uO3YtpdQ3TM5SZZCUevLBK7ZU9m A6RbS7cRCbyytjaEuH0WdwrjhmAwNM9PH8cBbdxgMbJUoqdO6Oo/CvpmGqnHKowBooroGw6e3wTw LBEDdM660oOCjSage44AXqr+27ZJ2+GI7o/VjsbeRiIjOztoVmVa6BxYhfKDgGS/oVSyidZt2vKy EtxJFA8zDjoTIAfguAEvatmlnHbLPcHTKJZZGmlrJ8zqOrqrItGrThgLeKCCFQsUaxqAFAQBRQcB l+OAzwHGE2z7jm9q8UgsdJoCt0ZtWjLUQ+nz8cuGAFHtH3RFpKJDquyU6DCG8EYFefUOqSajhQ4D ybavun04OilZQG9TqS8Ck15NFJKjl41wBjt33H+oZW0h26o/8sTU05/Fp8/7MAx2hZ/c1d2LbzbP BCARDJayTk1KODq9SOmPCla54Dothcb1Ayx3FrPcLKwLTO8Hy9RoRRNNQMBaXVqk8TLkkulljmAB ZNYoStcAldbfapLa3Er3Bki0QoIWk0njQsik1/E4DXLPer+2jvJm2qd02wyR2fUL84YdVpW5GZCw YLRhWgr8WAu7Obb4bsT3Aml3WWNtcvp5/wCXqUlEGjJFNP8AHjgG/ru39MSfO0M/TDennoX1aNPk /VlgDQblazzmCMSiVQGYPDKgANaVLKBnQ4BrATATATATATATATATAVG6tdRxyekjln1zL1gHaMpQ LTpnQ1VPxUB8cAK2ut60IPp55IGETPcEl8lprrGKN+OfHAAtp9zFkALO4J66Fdc51EgJpqTGp0t8 WVONSMBcQpF653DzdQqdcba+kPLwqNNfwPt9+AbwH//Z ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/journal/v94/n3/thumbs/6602935f4ath.jpg /9j/4AAQSkZJRgABAgAAZABkAAD/7AARRHVja3kAAQAEAAAAPAAA/+4ADkFkb2JlAGTAAAAAAf/b AIQABgQEBAUEBgUFBgkGBQYJCwgGBggLDAoKCwoKDBAMDAwMDAwQDA4PEA8ODBMTFBQTExwbGxsc Hx8fHx8fHx8fHwEHBwcNDA0YEBAYGhURFRofHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8f Hx8fHx8fHx8fHx8fHx8fHx8f/8AAEQgAlgCAAwERAAIRAQMRAf/EAIoAAAEFAQEBAAAAAAAAAAAA AAACAwQFBgcIAQEBAAAAAAAAAAAAAAAAAAAAABAAAgECBAUCAwMGCQcNAAAAAQIDEQQAIRIFMSIT BgdBFFEjFWEyQnGBMxYXCJGxUoKS0tN0NaHBskOzJDjRYnKiY4PDNFSEJXV2EQEAAAAAAAAAAAAA AAAAAAAA/9oADAMBAAIRAxEAPwD1TgDAVOy3O4payfVJ1uZnmkeGSCGRVELtqjT7uZQHTq9aVwDe 5zb1JcIdtuI4YAnzFmgldi9fSgFBTAI9x3CIZAJoDKSOnqgnoFyrUgCp/NgFbdNvkdwPqFxFPbgN Xp28yOSTynMEZU/y/ZmFm1/bKpZi4UCpJjcAAfzcA9LLHEmtzRagZAk1JoMhgGjeQ0NNYPoenJ/V wFP1O4wBS8hy46rWUk5epGkcfswCZT3Kzho9xijVQOUWcpDHSK6qmo5vhgLSzupEto1u5DLcAUkk SGRFY14haGmAb3KG03O2Ni7yRiUg1CuhOnmoG5fh8cAxYdtW1k6NE9dDiTmFSSq6B60yU/D7cBcY AwBgEXE8VvBJPKdMUSs8jUJoqipNB9mAyQ8ldre6V1vnFmI6dH2s+rXXJq6OGnKmATJ5J7cMOmPc GE3U1azaz06euummjjo5a4BR8j9vGWdkv2ETRqtuptbglJBqqzcgqM1ywA3kbt/p2wF+2tGU3Te1 no6hSGCjRy1bPAK/aN217tna9b2ZjC9I2s+oPqNWLaOGn0wF13H3Btmx7d73cJDFCziKN1jaWkjA leVQT+HAZlPLXaiwW4lvpDKtOu4tZaPQUbSKZVOAP2u9n+8Ym9l6AjAEPtpdQepJYnTw00wEdvMP aSWdG3NhOZcpjaTFdBk1BKADPp8tfjngHW8x9l+8jK38gg0MGhNtNqZiRpYHTwpXAS9i8ibFvu4z 7dt18Zb2bW1irW8iCMJHUh2YUJqCcBoNvg36Ocm/uoZ4KHSI4yjVPCuZGWAssAYAwEHff8E3D+7T f7M4DyPL273dJvMt5D3IIbJ5NcVtm2lDwXSeXLAXO22vdUEUqXe9WlxIWXoymGlFoagqGXOtMBoI 51GnXcRnIVpQZ048cBA3o71L0js+4Wttpr1lnTqB+FKEEUwESEd1fVC9xuFk211f/d40PWKleXmJ 41wHXfP23X+4+PTZ2Ext7qW6hEc6qW0UVyTQfwYDznc9i93zWNjAu8yJNatKZpRE3zBI4ZB/NApg JR7M379YbrcvqU3tp+potRG1FDxFF/osa4Csu/G2+z7OLE7rcGQXKXAmMb1AWMoVFKcSa4B1+wN/ O67beLuVx07KO3jmj6b/ADeiasT6c+A2HhLs3ftq76nlubqW/t7y2ukjtmDR0Lo3424ZGmA7xb9v 38UR07aVYMulfeMa5MGY1NT/ANHUBnXAanbpr2W31XlsLWYEjpBxJkKUOoUwEnAGAi7tJJHtV5JG xSRIJWRxxBCEgjAeZbLzzd3m7z7csu6xtB1uYlyGEANT+emA0O0eTNy3Gy91HdbmF6hjoxkBqADW nwzwFqneG7tcPAL++DICS2t9JoAcj+fAKbuzdlCk7le8xIHO/pgCbuzdl1Rrul2JgG0/MelVWv5M BvPKO63m19pvfWrzLLC+srbuySOFidtAKkHMgYDhV15f7rTtH65HbbsZzeNai0M83UCqurWRq4em AsYPIvd8nd8mzlNyWxSyF0Lz3E2kv0RJo+9x1HT+XAU1t5i7y/U693y5tt1juLa7S3W168+tkcV1 gauA4HAXv7T90Xe9l2qWbc1l3eGGVX68+lDKpYqx1ZFaZ4C/8XeSpe4t5u/a3F5cNtjTRzWtzNIE dlikZR8wleKcfTAdLTu67MLyGxjOimpUu4WoCCak/GuWnjgNHBPFMmuN1cepRgwBpWlRgF4AwEPe mjTZr9pQxjW3lLhKBtIQ101yrgPN8fdnaQPUXbr8MwqW1Wlebjn08BITvnttF0rY7gB8A9r/AFMA v9fu3/8A0e4f07X+pgPh797ePGz3D+na/wBTADd99uONDWW4UblJD2taNkfwYDrflzeLLaO1Iry7 gnuIxdRosdu0aPqZHFSZFdaUr6YDjD+UO3lBU7TudK8OtZ/2OAbbyz26pFdq3Spyr17P+xwCP2t9 tFafSdzofTr2fr/3OAB5Z7Ydkf6RuRZfuMZrOo9Mvk4DU+Ke7u1937zh22z2q7tZbmOeR3le2Mba Y2DaxFEjHImmeA7JHadpazbpHZ9R5CDGOnqMiMVOXHUGy+OAsbSxs7ONo7SFII2YsUjAUajxNBgH 8AYCFvcEs+zX8EK65pbaZI0HqzIQBn8TgPKK+DvIhmkla03RRIGpCJoAiFh+Hm9PTAEvg/yRItBB ukbVJLCS34EAUpq+zAH7D/JQkdxFugDAhU6lsQpIpX73pxwCm8LeVOkESO/VwxPUItSaEAUpq9OO AXB4c8qpdJI1vdvCGUmFlthWgANWD1zOeA7x5q7c3juDswbftNu9zde6ido4mRWCBXBYFyoy1YDz 9N4M8iPGY/pN81W1luvAG4UpXqcMBHk8C+Q2milOx3ZaGmkdeCh0rpFR1cAwv7v3kJYmiGw3ZVip zuIa8taUPV+3ACfu/eQVaFvoN2DAAE/3iH8LFhX5ueZwG98L+Je8O3PIVvvF/tc9pbiC5SSeWWJ0 VpEOnlWRjm32YDuA7b3BW6q3dutwZA/VFpGGHGtDxrwz9aYC5sIr2O2CXsy3E4J1SomgEenLU4CR gDAGAMBH3FL59vuUsJFivmicWskgqiylToZhQ5BvswDVk1/bbXb/AFFhcX6oi3DwLyvKaAlRy5Vw Dcl5uKwQEW7GUMhujp5dAHPoGomvwwDq3sxlciCRoaARkLQ1BIatWGXCmWAZhvr828KywkXlR11C HRpBGrSdXwOWAdS7uze6WhZLVkAjYrzdSrFtVCaLSmAhIe8RpVhYEADVITLUmhrRQPjgJFr+snuF 917P2wPOYurrIoeGrIc1MBZYAwBgDAGAMAYAwBgG1A1y8jAmlTXJsvw55f5MA2IkENuoSWkZXSNZ 1LQU5zq5vtqTgHEI68g0OKBecnkPHJRXiPXLANpRrZPlSgah8stzjm4k6uHrx4YBw/pgdLE6TzA8 vEZUrx/NgMXa2ViqFhs26RVGdXYs3N6Ubl08fTL48MA/fW9nM8TPtO6T6UTlV3VY8geUF1z+NMBo tijjTbIljingWrnpXRLSirEksSW48eOAn4AwBgDAGAMAYBi+vrSws5ry8kENrApeaVq0VRxOWAzq +SuxtTU3qM6uA0vy0yy5P48B8PknsYKgO9pVaEtparU+PJ/FgEjyj2BqZvrkRHDTR6Cn8yuASfJv YTRKo3+MEMD1ArVNGqR+jpQ8OGAdTyR2PNcose9xlm+WsQVqFmIoc0rX040wE/6Xfiije5V0mgUL EfQjPUGY/wAOAJNh3ORlb63dLoACBVjAqAASwC81SK4C0soJbe2jhlne5dBQzSUDNn66QBgHsAYA wBgDAGAMBRd9wSz9n7vDCuqV7dwi1C1P5WIGA82bP2d3xBczS7jMLmNwRFEnQQKdVa16meWWAtJO 298NKWpNP+0hz/6+Azx8cd1VuqT3NJ9egdW25NTahp5/ThgG5PG/eTwxILy5SSNnbqB7XMMBQEa6 ZUwFlsvZHeUHc8F7LcNJY9ZCbRjb0AqKcwkrkc8B6A/Vi7ae5kbbbMdfqliZZgzmQklWKk8p9csB ebJHu0KNBeQQQwoKxNC7MSWJLag3DM/E4CzwBgDAGAMAYAwBgKnuyOaTty/SAVmMXy+UuAQQQSq5 kD1AwHP9uTeUEn1GeKckjpe3tZogBnq1a3lrX04YCWTJqBBYLlUdGT/kwH1WP4g5/JFIP82ArdwT uB7yI2M0EdkAvWimtJ5JCdXNpdXQDl4VU4AsI9/9zKL0wS2zVECwW9wktSw0hi5dTy8aeuA1j7Xv P1G4KQXpgkMpE3vFA5tRCohHL/zW9K4C52KXdEX2t5aSxqgZxdSypIWLNXSdPqK/kwFvgDAGAMAY AwBgDAU3eVf1X3KnHomleHEcfswHnO3l8lvZ34uo9oiux0/YlJHaNuf5mvlqOXhlgCabyGke2rHD tcrsv/yUnUdQrGVv0YK1I6dOPrgHXn77FzulIdrNuqSfSyJX1M/UHT6tVoo6da09cBAvLryT9NtH hs9s98ZJhcxdc6AlE6RVtOZPNXAXG1Xvdrd4Lb3FlarsevlvUmUyfcGn5dK5vlxwHbrt94a8nnjX cljWQFIUMOg5aeWqltGWfE8TgL/br2W7iZ5LWW1ZW06JgATT1FCcsBKwBgDAGAMBB2XcptxsRcy2 slm5Zl6EoIcUPrVVz+NMvgTxwDov4erIjMgVANL615ia1FK5UpgG4tyDW1tM6CNpyNcbOtYxTOvx p64BaX8b3bwDT01jDibUukkk1Wn2AVOAbl3ONLV5VRXlViqwB1qw16Q1fgRzYA3DczZiJ0tZruKQ MWa3XWVCgEZeuquWAi/rC+nWNpvyor/qlrl9muuAsbK5a5h6jQSW51EdOYANl60BbjgHXkijFXZU HAFiBn+fACTRPTQ6tXMaSDwy9MArAGAMAYAwBgEsXDKFUFTXW1aUyyypngG4o1BePoKkaUERFKMK VOQ4UOWATHGOnHIbZUlenUTlOmv3sxx4YBbQxO+l4VMdMmIBzNQRT8hwBp+WzdFdYrpTLOnDP7cB Hvbm4s4oks7FrnVUdOMqgQAVzLYCJBum+vMiS7O0cbMA0wnjYBSwGrT977tTTAXGAqNwvtsniuYb y0knitZVjdOn1KsU1AgCp4HARdvbbDue3CxtGtk6FyV1QtHRdaVWpH8rOmA0OAi7q7ptd46MVdYJ CrA0IIQkEHAQ+3beO1ivLSIv0Le5KQrI7ylVMaORqkLN95iczgLQyxCRYy6iRgSqEjUQONBgMZ3Z vnell3Fb2m07Pf323TJEZL21FkYYmaRlfX15Y5TRaMaLw4Z4B6DcO5QpaVr05jI2cdaZ8ArcPy5/ ZnkGrkC9WOqsSCaFSdIy/FQ4AQL1JaKwJpUkmhy/DngG9ERhgBjk0qylVq2pSOBbPMfGuAWET3TP pbWUClqnRQEmlK0rn8MA2WjFrM3Sl0gvqj5tbUJrpzrn+HAQO5Rt/skF612sZLALZ9XU3Kcm6fpT +VlgKC2PbkcepYt0jQaSdYkq2f3uOrT/ACqcvx9MBpN4Mcnbt0Q5hR7ZqOwJZQUyqMzgIm3G5T6r 7Dpy3Qli0pJqRdXRjrqIB4rmKYB2N9zbdtvN7HDG/RuNQiZm5tSU4gZacBc4CJvH+E3v93l/0DgI mz3MJvtztqnrLOJCulqaWijAOqmnip9cByzu/ubuC2/ee7L2GC+lj2e72ueS5sQR03YrdEk5V4wp 6/hGA7TgDAcX7u7+73sO5dys7O4lS1gn0QqsETAJpByLISePxwFBJ5U8jLXTPOf/AG0P9lgKPe/M /ma1eIbdbTXiMG6hMMCaSOFKxZ1wEKLzh50bcejJZSpZ1/8AMdCEkDTXh0vjlgLMeZPLRH+urUCn touFMz+iwHQ+we9+7d27fnud3vWtbtLvQpktVJ6QhDMqqioDRmrXAbG07keCWNr++DwMgYqttIpq dQqTTLUaZUNKZnPAW+/yKe3r6QV0m2kYUyNCh4YCv2+3Vhu6tcNZh5YD11YKygQRUNWqOamAetoF i3TbtN9JeDo3I1O6PXmQ6qqBn6YC8wETeP8ACb3+7y/6BwHD+17y8P73fdVoZ5DarssTrb626Ybp WeYSumuZ9MBX7/uF1f8A71/YlxPa+1V9qnNupdZC8LR3hSQ6fulgc19MB6LwBgOXb7IE3vcFkZdR nYjVMgNDSmRkFMsBSTvOSQjx0zp89Afsr83AUu6w9zSov0+7ghYE62kmVgRTKlJ1pngK5tv79M0Z G524iATqIJFqxA56H3GVTwwFbFsXlQRSq+/25kYL0nDR8tGqajr51GWA6R48se7IO2549wurm/vl ui5k2+WNCyFAAh5pQvHAbW2k3q0nhnkg3G6QR/Mgd42Uk1GedSRWrfmoMBo7y1F9YSW7s0InTSxW moA8RmCPswEFbeNItyF1avLavICID80OoVRVU4UJFdIwFa24bVZ3NldQbfNAiQThIltysjapEVY1 FPvM5rpr9uAa2Tyd2v3DFvi7JNJcXewSC23CBomjaOdyyqvzNANHRgc/TAZftTypuPcfdPefaF/Y LbTduWgD3COCJJChWTlHAFjUcxwGV7W/4xO6/wD6SL/ZWWAib3/xR+Nv/wA//wCDeYD0XgDAce75 8M909xd2/WrTfpLCzSRHWximZEk0PrOsdJs24HM5YCok/d+7ok3jdNxbf5tO5xTQ+1F04jgE1OaL 5ORSnLgIkn7tW+yduQ7G2/XGiG4a592Lx+sxZdOgnofcHED44Ca37vu/ne9r3X6zKG2uOGJbb3ch imEIpqlHQzL/AIvjgG7f93ruqD6to7juG+qRmNS907e3JcPqi+QKHLT+TAbjsLsPf+1O0rnZ728k 3m5mlBFz1yk3TPxlKqRp4D+PAaParfdrO7Oq1meKYqJJZbsShcqswQgeuWWAv8AYCj3Hbd6u7i1l BtgLaQvQmQVAlV1HA/hjFftwGD8f+I967WvO77xdwtbxe7L5b4Lokj6GmaWXRXm1/paVy4YBXavi jedo757w7tTcLW5XutGjFrpkToEMQefPX/AMA9tPi7erLzJu/kUX1rJ9RsksDtmmRemVSBdfVz1f oOGn1wDV74n3u68qdt98C/tVPbu3iwbb9Eh6tUmTqdX8P6fhpPDAb9+6NqRitZXpUM0cMrrUGlMl +IwFja3UV1bpPFXpvXTqBU5GnA/kwDuAMAYAwBgDAGAMAYAwDduSYVJDA04Pm358AQEmMVDDM5Pm eJwBDXqTZN98fe4fdH3fs/z4AQt7iQaWACrRieU1rwH2euAw93czDd3T2W5vRyFleedYyNZzC9Mp pp/KNKYDTdtyyyWcmuC4gCyEL7p2eRhQZ84DAUpgP//Z ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/journal/v94/n3/thumbs/6602935f5ath.jpg /9j/4AAQSkZJRgABAgAAZABkAAD/7AARRHVja3kAAQAEAAAAPAAA/+4ADkFkb2JlAGTAAAAAAf/b AIQABgQEBAUEBgUFBgkGBQYJCwgGBggLDAoKCwoKDBAMDAwMDAwQDA4PEA8ODBMTFBQTExwbGxsc Hx8fHx8fHx8fHwEHBwcNDA0YEBAYGhURFRofHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8f Hx8fHx8fHx8fHx8fHx8fHx8f/8AAEQgAlgBtAwERAAIRAQMRAf/EAHcAAAIDAQEBAQAAAAAAAAAA AAQFAAMGAgEHCAEBAAAAAAAAAAAAAAAAAAAAABAAAgEDAwIEBQIEBgEFAAAAAQIDEQQFACESMRNB IhQGUWFxMhVCI4GRUiSxwWJyggczU5M0NRYRAQAAAAAAAAAAAAAAAAAAAAD/2gAMAwEAAhEDEQA/ AP09isZb4yzFpbtI0Qd5KyuZG5SOXbzNv9zE6AmWWKJOcjBEqByJoKsaD+ZOgWWOXlucrNZ8V7UX d84rUmN1Wm/+7fQNdB47pGjO7BUUEsxNAAOpJ0HBuLcSCMyKJGpxSoqagkUH0B0Cse21E8svrbhu 4XPFnJCh+oX5AbD4aBwOmgmgmgmgmgmgmgmgyX/YXvf2/wC2rSCPLztbi7YNFIONP2XRmFWZd/ho EeF/7M9tX15xxxJ7kzAOvJjVgKGXjI25b79jtoNvjs5Z3Yij7nK4cbhY5VUkb7c1G2/joBPeOex2 JxbLesUF6Ht4mqoHJkPUsy6DORe78PPmoLysvZBhEVEUgnhJG1aN0rICKV8dBsLfP4q4kjjilYvK eKAxyLU0r+pR4aBhoJoJoJoJoJoJoJoPlP8A3jFi5GxIv7VrsATFEUcqbx1JHJRoMr7VxHtW0ydj c2drcpcyXKgKOQjqGBBkIY8QfjTQfW8ScbNOkc1sbaaoa3CzXDhj1NSyoP0+OgTf9viD8RYmWz9c BcErAFjY14HcCVkTb66D59jrwR5HHwJjpUgZ4WJBhWKKrg8GCS8gR/oU6D6xi/xks6xT2xt5C3KD hNcvVyfNUsqAbr46DT6CaCaCaCaCaCaCaDl4opKdxFenTkAf8dByttbqQViQEbghRXQWaDl445BR 0DgdAwB/x0HItbYEERICNwQo0AGQyWTt7sQ2+Oa5iKBvUB6LyJpxI4sfnXQHWssssXOSPtMSwCGt aAkAmoHUb6C3QTQTQTQTQTQL8Xb5m1xZjvrpMhkFMhWbgIVarEopC1pQUFdAru877jsMjZesx8T4 yWOb1j2ztJcRSK6CFljoA8ZVm5U81aUB0D61vbS7jEttMkyMAwKEHZun+GgE9xSTx4S9a3vhjZ+0 RDfmL1Ahc7K/aJHOhPTQKZ82Y2CjMxjZOX9o77sob9J25Cp+WgNHufE2sfavb0NdRgdykTqWruCq AMaUOgdAggEdDoBRDfDJtMbgGxMIRbbiKiUMSX5dTUbaBZnrr3dBbXL4mGxaRTH6X1TyhWJlQMr8 BVaoWofjTw0HNj7zxtxkbTFzxTWmSu0mYQSISqtblBIjSLVA37g4g/d4aB/oM0l5cQi9Mucd/wC8 ftmS0VVgjKAiAcQvMLSvM7nQW2metYe7JdZX1Ua0AQW7RsGJNOgJatKDQFj3TgzbtcCdu2jKjftS 15MCQOPGvRToD3vIFuktCx9RIjSIlDuqkAmvTx0CyIy5C6j9ZZtZu9vMpVnVnFJIyCCtfqNAg9uw 2OLyOYv7KxltmmyLx5vuK4E1xwSlzCGr+24I402rUaDVZSK7v8RcxYq/FjdzxMtrkUjS4ETkUEgj fyPQ+B0A82JzEkisuYkiUKAVSGIVYKAWJIPUiugMsrS5hLG4uTdE/YWRV4DxAI33+Z0BWgpvLuCz t3uJyViSnIgE9TToProAMpcXjM0Ho62oMLC6LrTl3VqOH3VXroAs17bsTll9xx24myEMJtpFb9Vu 5BkUfM8FP/EU+YXe3JZxJdrJkvyNtcymfHMVUGCHgim2LKSXaNhy5Nv5vloLPw+b/uK5yY925M0P 7EA7UJQKIFoo5AN5uTVOgtGOy4hdPyjF2pxcwx+WlK0Hzoevx0FYxOb4FPzUhBIo/Yh5ACtd6U3r 8NBRZ34vs1BcBO2EjuoRGWqxEcqLy47eI0BNnereZCGYQTwfsTDjOpjOzx/pJ0Ez2PtLq0nju1LW N5C9nkUDFCYJQV5clIK8OR3B2BJ0FXtq3hxkT4SMcY7Pe3FSaxMa1qeu5qfroHWgmgmgQe5r6sc2 O4hQ0AuDMWIA4zKoWgHx676AvKXtWa0NtOQDC/qAtIv/ACrsGr1HiNA00GQiw9v7a/IRYm0LvcPL lLWFW8012Eo8fJzxBlVAngBtoNPjbxrzH2120TW7zxJI9u5BeNmUFo241HJTsaaAjQTQZbCrF+Zt 3jDKtL8kNTq06Hah6eII8NA1tchaX2ShltpGdBBMN1ZRUSR/1AaAvJ462yWNu8ddcvTXsMlvP23a N+EqlG4uhDKaHYg1GgzeWt85CMXcYuSJPxEwiy6yhmlls1Q07exHJqqxLeHLeug1cUsc0SSxnkjg MrfEHQdaCaDK+7Uia4uKq3c9DTmKcQpuIzvuOlK/z0DfK39tU2PJxcVhkoEanEyqPupx0DPQJ/dl llrrCzfhmjjy8Q52MkwJjEg6cqVJHjTx0HGHySolsl3LGst8BxAPFTdBeU0cYO/moZFHWlToHegm gXmAR5eExxskKwyciu0XJmB6Afdt1qNB5DfWl1lIWtp0mUQS14EN0eMeGgY6BVlUysV9Z3VkkUln yaPMRycjI1v22KGELsXWUiob9JbxpoFuCytzDn73DPaSRYuMI+OyMhHbuDIokKw0rVU5UYn9X10G n0E0AGagMljKY42achVVotnpzB6gMaDqRTQcZS/swptO+i3XKF+0SOXEyqOnz6aBloJoMdmxBb+4 7C0lxrzxTTG5tcj21aKxuFik4zMzfbXeM8d6P4AaDVWl2lwhGyzxnjPDWpRvgf8AI+I30F+gmgAS OGPJwpAqJGIZqqgAo3OOuw20B+gldBmsjhZbQ5K8FzLPa3DC4htmIC2UkcYBaCgrwdl5yA+JJGgL 9m5bI5f23YZPIJbpPeQxzr6SUTwlJEDKySLsw36jY6B1oJoAcosQhLAIJ2aPc05FRKlfnoDtBNBV dW0VzA0Mg8p6HxBHQj6aDPe1cdeW+XzN1d4qOzkm9PDHkVl5vdxwK6rzjr5O1yIX4g6DTaCaABsP aG+E/YhMZWTmGQM5eRlYtU/7d9ArusVPbWN3JO1kqllKyemJCp0bkoJJJ26aAdXs5Jsce/Y8W4dx DbENIzEqSg/SCNt9Ad+Cvf7skWJMv/x/7bZfN+sEmvk20BmIw9vY2cETQWyywDijW8KxKqjZQo3p RdtAx0E0AeTxsN5FQxxNMKCN5U5gDkrHb/joBrjChr6GWGK1W2QUljaEFiD1ow28B4aBN20j9fbT NaC4HEh/SMEWpCtU/qqKDy6Au1x8t5bWc1sbNkQkTs1qVLkNTyhiCvl23Hz0BlrhWS+mkuI7R7V6 9qNYAHG/lqTUbD5aBr2Yu12uC9qnHt0HGnwp0poOLa7tbqITW0yTxEkCSNgy1BoRUV0FugmglB1p /H6aAaHJ46aNZYbqGWNiyq6SKykxtxcAg/pbY/A6C6OeGUExSK4HXiQev00A+QjybhPQyJGRXmZB UGvTan+eg4xs06lrO9uYpr9R3CiEBhExorFaA9QRWmgO0E0E0HPei5Fea8lIVlqKgncA/XQdVHx0 E0FFjYWVjbi3s4VghBJEaCgqTUnQIM17UguWsit5erdQ3fqLOcXD0ilWCVRVftZCGIKsrD5aCrHe 4fcMWZixuSskfHuAq5oOqEz+YG3ktxy4yKVHmB4sGBX4aDVt9p6dPHpoMdaR2Qw8XpUwC2ncnPKA r6XudzzcQoC8jJXufP56A2zlvIokGMOKaaUkSRwMUVqUAZePKvHeo0D2xF+LZfXGI3NTyMPIJSp4 05b9Oug9FjaLetfCJRdvGIXmp5jGpLKp+QLHQJPdWAhvsZfCS8voVuUWNha3DwslXXzRslGQ7dRo M9Pe+8sd70w+La4nusciXD3F24iWCYMoWBJ2Ch0k51AKVFeqgaDYYn3BY5O7yFlCHS8xckcV9BIp Uo8sayrQ/awKt1UkaBIcXj48rmrmPG471F1NC15KkoSeUrEVQznwbhsK+Hx6kCrGCe1aWaxxVpHM UKqyXNQQWFa+TYbVOgvGWzvp2Y21n3KgK3qvIRvyJPCvw0DDI3sttJZogU+pnELcq1AKs1RT/boK Da3EV/FJLeSTJLcFooSqhYx2pPLVRUj6nQB5T2/jBkrjLOjCS/hhs76QO1AkLu1vIFJ4go8rVIHQ 77DQcez8xm7yG5ss9ZCxydlI0fESCQTQ8iI5gRt50oTStCaddtAzi9v4GG3W2hxtrHbozukKQxqi tI3J2CgUBZt2+Ogvix1hC4kitoo3HRlRQRX4EDQEaATL3r2WNuLtArPCvIK1aHf5aALM290YZLk3 bpb8I1Nqqrx5cweXIgtv00B+RsIb61e3l2rurdSreBGgzGBzeWupb5r6wks7rDydnk7A+stQoLSK NmqjVpUb+GzV0DHF4b2XlYHz2PsrS4jzghvJb2ONa3PGPjE7tTzUQ0FdAwGAwojaMWcQR1CsKdVF KD6Cmgr/APy/t2v/ANdb/wDtrTQK7u7kbPGGZ2aOK+tVgToq84Hao2NamtdA0ZMgl/Ebm4jeF7g+ miVOLBe1JsxJNSPloGUkaSRtG4DI4Ksp6EHYjQYy8bP4rAyX8ytmPcGHd6x2kfBri2klJiUKSfsh YBj4lWOg1WLvWvcfBdNH2nlQGSKvLg3RlrQVofloCtBNBmvdd5LFJJCzN6U2NxI8a7BmVkG5o3g2 2gNy6ZHsu6zxLY9uMGNkJk58xXzcgNxtoHGgRe6GWwtznFB5WS1nUCvOLoRT+P8AL6DQce2MlaHG 2DxW5x9hkIklsLSZBC8DuKvatHtxZD0X6jw0Gg0E0Gdvbe5GYSSbisMl9A0AbgpYJC6sARu1DuAd Axdskb+ITrCtsJz2SjMXK9p/uqAAdAx0CvOZGxw6DMX06W1lFxivJpDxRUkYLGxPykYD/kdAu/MY 3Be47fB3M4jOZ5yYuGhJLRcRKoABoF5rudumg0ugmgz3ui3uHWaQcVthZyxvI/EAO7LQcjuK0ofD QF5hsh2GVIojZdtCzsx7nPmNgoBFKfPQNtB46I6lHUMrbFSKgj6HQY7L2eCiu7fD5mSNIpruG6wL StQrfRNyh4bjkysPt8fH7tBqrG6NxBV14TRkxzx/0uvUfQ9R8qaAjQD3dtJM9uUkCLDIJHUivIAE Ur4ddAK895JfwpLadqGOciKcurFh2pNwoFRoGWgruLa3uYXguYkngcUeKRQ6MOu6tUHQZ7JG0GRt MDfQyu9wksuLygj5JCYSg7ckx+yQ8xw/rAPiDoL/AG77ngyN5fYh+RyeJYQ3zBCIy5VWHFjsSVdT t8dA+0FF/byXNnLBG4jeQceZAO1d9j8RoF+amuxA9uLQyW/BGa55qAG5jbid9uugb6CaBXnPb2Oy 4hkuIka6tG7llMwqYpNqOPmKbHqPCmgS4C/xd37wu1kvJV9xWlikF7jQ1IDCJm4XPDjQuWDJyB6b fDQa7QTQLr+6dby3RbWeXtSBu5Go4+aOQdSy9NB3+UfmV9Dc1ABrwSm9fHlTw0Hn5ZuBf0N1QVFO C12NOnKug5nvllUwS4+4dJAeSlEKkD4+bQBYeXKWj3y3TXd9FJcc7JHhjRoIe0gEPPn+75gzczvv Tw0D1TyUGhFRWh6j66D3QLM/cduxePszS8xWsKF6cWXY8d966Ds5qEMFNtdVPT+3k8P4aCDNQksB bXVV2P8AbyfCvw0Hn5234K/prvi9Ap9PL+rptx2/joOUyVkkzsllcLLJRpHW2cFvCrMF36aAz1i+ l9R2peP/AKfbbudafZ10F+gHuvS96271e53P7enL7+DdabfbXroFkg9u/kbzkX9X2ZPVU71O3Tz0 p5a/7d9AjNzjhiWMllWyFyRCqTXAJfgdySvMbfKmgcQHBNfWTSq8eSMURijBnZQOJ4itOB2r1/jo L8CMCJbj8WXL+Xvcu7TqaU7m3x6aBxoJoB8j6X0Uvq6i3p+5x5VpX/R5v5aALIjC/k7T1ZYXtV9N x7tK8jxrw8vWv3aBG0+KS5yqxWxktVjJu5O5OHbzeYAMAB5q/boLIZPbkuJtzfwvbwdyQWyK9zJ4 jkSVAPX+ofTQNYhgfzxKF/yniD3uP2D4/t/boHGg/9k= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/journal/v94/n3/thumbs/6602935f6th.jpg /9j/4AAQSkZJRgABAgAAZABkAAD/7AARRHVja3kAAQAEAAAAPAAA/+4ADkFkb2JlAGTAAAAAAf/b AIQABgQEBAUEBgUFBgkGBQYJCwgGBggLDAoKCwoKDBAMDAwMDAwQDA4PEA8ODBMTFBQTExwbGxsc Hx8fHx8fHx8fHwEHBwcNDA0YEBAYGhURFRofHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8f Hx8fHx8fHx8fHx8fHx8fHx8f/8AAEQgAlgBqAwERAAIRAQMRAf/EAIwAAAEEAwEAAAAAAAAAAAAA AAQAAwUGAQIHCAEBAAAAAAAAAAAAAAAAAAAAABAAAgECBAMDCAUGCA4DAAAAAQIDEQQAIRIFMRMG QVEiYXEyQiMUBwiBoVIkFZGxwWJyM/Cyg7M0RJTU0YKSwtJDU3Oj02R0dTglFnYRAQAAAAAAAAAA AAAAAAAAAAD/2gAMAwEAAhEDEQA/APRm03Wi1ey2y1C8jU0aSzMwIaeRWq5DtxQnAS9pPJLGxlQJ IjFGVTqFR3EhcA9gGL21a5tzCs0luSQebCdLihrxoeOAVnatbxlWmknJp4pDU5DAP4CK6jigkt7Q zRiTl3cEkeosArq1VbwFa0PYcsAorjcnt7e+M6CG4Fv92EfAysgbx6q+sezASuAWABTa9N21x7zO 2p9fKZ2KDMGgFchlgDsAsAsBXNnu0juLuUxsyqrN7JGZmBupxko4/kwExtrK8crqGAaVmo4IYVoc wcxgC8ANeTxqOSWId6UpUZVzzHDKuA1hvYBHChcu50o1PFRiB6X0nAF1FSK5jiPPgI3fXdbe301q bmEZcPT7fJgBLe5lfa9viNqxj02b+8Dl8uvMjyArWo82AncAsBxPffizt8nX3Tm9W17dwdM2Nr1G N4tqMokfaljDsYVJEmg1KHAdM6X662Dqa73G12p5Hl2sWpuuZGUFL2AXMOknj7NhXuwE+rKyhlIZ TwIzGAzgIHp467u5kNBk4AFKilxLWprXy4CUsnWk1WB1TPpPf2/mwBHNirTWtaA0qOByGAjr9lN3 FQg5oP4+AYgYeyqRTUP54YApLm1W9eUyIEcUElRQ5JTPANb7OjWluY3Uh7mJNS0btzpSuYpgNWlh i2exWSUIxNsRqYVIWSPV6VPpwBv4rtlae+QVqVpzE4gVI44BDdtqIBF5AQaEHmJwbJe3t7MB5F3G 3uDtjgROTyOvBTSeMunl/wCX6vf2YDp/wcurez3Drc3cq23vMGyR2xlITmONnRSqaqamBFKDAWL4 Cb5tFh8IumrK/vYbW9hs9c0E8ixyIslzIiFlYgjU2QwHUebF9tfR18R6Pf5sABEl3CzpFt0KRA6V KyAFkJYnLRlxrTy4DTaYYZbRGaNH0yOEqqeECoAFEThw4YAkWlqUB93i9FPVXvr9nswGfdYBXTCg zY5KvHsPo4DPusBIBiQioy0r9n9nvwGi2tsAtIY6UT1V9Y0Pq9uAUqyxWv3MQJKXNOb4UyJHqgZ4 COe9vbieBJIXQiUEOiTJ4RQMCaEFSfLTATNDqGWWo9h4U82AxRqDIcF7+Nc+zAIq/f8Aa7/o7MAq NUceI7+7PswGo16RxrQfa4182AfoMBVE2y/jheMQSHUpBohFSaf9VgJvZYZ4bFElRo3DtVWFDSn+ 8m/jfRgDNLUr20UfkP7WARDEHI+t/DjgMgMCMsqj83nwGNLZHtotfoOfb/Dy4CP3mwlvIIQseto5 C2kiI9hFfaCQD6M8BHJs14Lq2ka2XTEVqxFtUAPXKkVcvIRgLHpNeHaT2d3mwGoQgAAZAKKZZUPm wCKV7M/FQ5dv0YDIU14dozy7vNgMCMgAAZAAUy7/ADYBzADW0Flt1rHbxkRQKdMYdic3bIVY1NSc A2NwZ5ZIuU0QRZDzHKUOjTmKMcvF20wFK6d6/sdzSd7Lqnb97EDRCYWfIPL166B/aL6enLPswE1D 1Fd21JbqQXEUlVCVtYdLCnA8417qYCywyrLCkqEFZFDKQQRQivEVBwFX6M60suod46l2+2a5MvT9 8bC694WJUMgFaw8vPT2eLAWvAB32z7dfOsl1FzHUFVOploDX7JHfgCY444YljTwxxqFUE1oFFBmc BB9S77Ht+3z3734stujtmmkvyivHGoBPMr4q07tOArvT3XNpu1h71tfUKbvbs8kS3MSRRrrUKSKO i5rq+vATlr1DLbTxwXUouFm0FZZJYVZQ1PVjUV/TgI/bOvL68+LO9dEvaxLZ7Zttvfx3YLc1nmYK VYejQVwF1wEDvKqd5tKuFJEekGvEXEZ7O/hgH9vj07pNVNOrnVrHElfFHn7Mkt52zwB0G2bbb6vd 7SGHVTVy41WtOFaAd+Ae5EGQ5a5ZDIcDgAt53qz2e3hkuFcrPKlvEsYB8b101zFBlgOYfA0sesvi mWGlj1C1VrWh0HtwHX8AsBHb6B7nGSQFW4gJB7RzFywAu3xkfhQyeP3dQHCZHwN65NfopgJoKoFA AB3DAZwHI+nf/Zvqz/wFl/OLgOuYCG3WFvxW2nZA8QVEGpSQHM6HIgHOlcA7Zxhd4nOimrmHVojW v7rtQlm87Z4CUwCwFT+Iv9A2z/yMH+dgKL8HNxsbHrP4oNdzLCJupTFEWNNTlGIUeXAWX4f/ABJ2 /fLjqGK5jNi2273cbJba5nnNw1sARIAVGhm1ej5sAf8AC/rS36u2rdL2CCa3Ww3O52xlnlEpdrUr WUGi6devhgLHvMLzWsaoK6Z4XdaaqqsgLV+jAC2aqZdscRhRyAAVSgHgbINkf8WmAmcAsByHpqRZ PmZ6sZeB2CypUEf6xe/AdewA24Xb2lsZ1RXCka9TFQAcq1CufqwEfZg3d7cvE4tnSlTDy2LaqV1V StfAOOAKt4buWAOb2TxdoWI0oSOOgccBpbRXV1aLIm4yjWah0WE00mhArHTPzYCPn6cO6WyPfblc zosyXMMZ93CxvECAFZIUJU1z1VwEPtfwy2Gwl3HeYri5W43W/G+XYaSNoxcqppoPKFI6HhgFsfwz 2DaBd7pZ3Fzzr/cZeoJxJJGye9zqC4UiIUj8OQpgJXoboba+kbG7t9smnaHcbybcrlJ2ST7xc6TJ pZUTw+HIYCwXczwW0kyIHZBq0ltIoOOdG4DyYCKiuJb+/QxtFC8cOtHHtGq2RqCENPFgC4F3KQS/ eo6qzItIq0IPH0vqwAd5t9zvO23dlJf8uN2MTSQJpdSjhsjq8lDgIjYegLSx64v+sUvZJL29s4tr mt2CmIR2pAVwRRtZ051OAuWAi7S1t9wgF5Nb3NpLMSXgeWRGBU6fRR9IqBXAHQWkUDOyFyXpq1u7 jLuDE049mAcjjWNAi1oOFSWOefE4BRxrHGEWukd5JOflOeAxFCkcfLXVpzPiYsczXiSTgMrGoiEQ rpC6cySaUpx44BcpeVys9NNPE1p+1xwDFxP7nFEEhlnWoSieNlFPSapqcA21ja3oW5kWaN5FFU5k sRHkKowFcAj+GWDtNLccopHVubMxAjHrUdiPV44DS23rYnV2g3CCRSWZiJlalKFuJyArgH7G7sLh HazuEnXVVyj8yhbPvNPNgHookj1aSfGdRqxbM5ZVJpwwG+AA3HdfdJooFjLySaTU5KFaVIj5a+0w DNrPK+5SoZWdV5oCl42ApooKRgEUr62eAo/S+53F1JdGDZ+orB4THU7rHMiSGrfutMrVAp4q9lMB Y4m3az0zwRzPI+pXWRbqYcR4tLPQZ9v5BgLNbyNJbxyOpVnUMykFSCRmNJzGAofw86v3He+teu9p uo40t+n76C2s3QylnSWNnYya3dagrlpAyywHQMAsAxe3a2sSyFS+t0jUCnF2Cjj2Z4CC3N9x3Db4 3sFtzuNzalraC5P3fmNG5Xm6V52gnI0wEdsWw9bC0I3ldqt7kyN4Nqe4WExlVArzEB11rXyUwEqd m3lZ4pIpwAukyAzzAMQamoVQCPPxwFE2KSQ/M31NGXYxjp20ISp0g85c6cMB1vAQe8am3e0RI1kb lhnBOegXEWfEcOOAetG/+YlXXq0mXi0TUryzwQBl4+tngJbALAV/rbdr3bNrgltGVXmuooJCyhvA +rUM/NgKD8GlVfiZ8WFUBVG62gAGQHsXwHWLe8gnd1jJJSlaqy1BqKioFRUHAB7Lv+3bwLo2MqTC zma2uDHJHJomT04n5bPpdPWU5jAZ35qWcVAC5uIAgJp4jKtKZjPAD2SlX2tWURsIV1RgpQHlvw9f 9GAmcAsByLYf/Z/qf/8AO2n88mA67gAr7bveJ4p1YB46CjA8BIrnMdvgywAwmSHd3adxGlHoXeOl CIwMgFYV/WrgDhuO3kEi6iIFKnWuVTQduAwdz20KWN3CFFKtzFoK8O3AU7r3fNmvrCO0sr6C5ubS +tjdQwyI7x6w5XWFJ01HfgKB0Xvl3s/xC+JU1sqE3nUFjBqlBK8t4JNTLQrwpgHvh51Nv0HVHWNt LeSTRT9XyWaNOzOI7YinsA5KovdTLASny6DRb9doxozdXbmy6siy+z8Q4V84wHWLy1FzEIyaaXSQ Glc0YMPzYCP0x2U9ik8qIIY9LMSiqKI+dW8f6MAeNy241pdQ+EVb2i5DhnngBN06j2rbtvnvpJlm jt1DPHCyM5qwXIah2nAct6Uu1uPmS6guSylZ+m7JkIyHilRgvE5iuA7LgIzdrsGKSCMXCzIVKtHH PpJ4+nEpy76YDG2CRrmcS62XStBJzSK1PDmKo/ITgDLSNDB4kFdT8Qa+maekAcBrYx1thzUXXqau RPrGnpgHAZsgrW4JU1qwOoNX0j9oA4DFvH9wTIs/LqC+qtSK5kjV9VcBiFD+GprFZOUKnxFq6e8j X9VcA7aBfd4jQ10KKtXVw7dQB/LgBN0u0EUtuFnEtAVeKOYivEeONW+mmAY22N5LxuerOOSARIJS Kgj/AGqAfXXAHWttblZKxL+8cZr2av1gMvqwGtlbpokMkKA8xwKA+jqNPSA/wYDaySIq55dGWR6E qQeNRTUB2HsywBWAH2+0e0s47d7iS6eMEG4mIMjVJPiIAwG1490tu3uiK9wR7MPklf1swaebARz3 XUMcJMkVqrkqqsWYLVjTv7TwGAKhm3T3VufAnveekRmsfbSpJB8+AGlu9/jid3htowBk7SNpGY48 MAbYSX7RkX0aJMDxiNUI7OJrXAE4Bm3tjC87mWSXnPzNLmoTwhdKDsXw18+AdU5t5D+gYDBrrXM0 zqOz82ATkgCneB3cT9OAE3mSWLbpZIiVdSpBDaPWAPi0yfxcBAteXsirAlxK1w70VUuFGYyNWEGV GywBfI6i+xL+70f0qPj9r9x6X1YCwYBi8uxbJGxUvzJY4qDKnMYLX6K4CM3F7iSC6SQhxDeW3KUe A6NcTUq1ATUn82Aea+ltZNxkkrLHFJEIo8xQSKgoCRTia4BneXuJLXdYXIMaRRtCvomhrqqxoMyu AOgeb8UukZiYuXC0aGvhJ1hvJnpwBmA87fONeXVvtHSiw3s1ikt7Os0sDup08pcyEILU7sB5c3Lc 9yt0LWvUt5dEerruIzx/WbAbWu47vIgZ+o7pCRXSZbnj3ZHAMrvfUHAbre/2mb/SwHoP5St53xZu qpHmmv2VLEKlxJPNpBaepUASN2DswHqLbbue5hdpoxG6uV0gOOH7aofyZYAvALAcF6/+YC+2DqW+ 2ee1sBDZXRW2eZ5Fd+UQQxowHHAQLfM9cxiV2ttspM4kkrNK1WUACg1nLw8MAFB81zXstxC1hZRc 0q0rStOiuUoBpJenq4A1vmeuOZOxg2stOF5wM0tCFyFBroPLTATHRfzFXXUHV9htUVtt5k3CeG3u GheYuI9emqgsVy1YDvVpeW93EZbdtcYJWtCuY4+kBgPP/wA4m5tYbJ0zp2+13F5budUjuo2loeWv oBWTM4Dy7P1JcwqXn6X2qNRxLWsg4/yuAJG97ikEc/8A9Z2hYZVDRtyWzU9tOdXAO2O9bje273Fv 07szRRNocmEqQaV4NMDgO9/KZ1CDedU8/bbW0MaWKn3CIqTrab06u4oKYD08rowqrBh3g1wGcAsB 5t686I2q/wCsN4ubi8zmupG5b2ySaeFVBaUVGXdgK4Phh01mRMn9hj/52A3l+HWwMoEtypVfRDWU ZA/42A0Hw46cYH260rn9xj4j+WwE70V0ZtVj1ds1xDdHVDeQFVW0SPUdYoNQmNB9GA9Frtm2vIsi rV0IYFZHyOVK0byYDhfzfWOy3ex9Npuk91Aou5+UbSKOUk8pa6uZJDQZdmA8wnp3oYf1/dq/9pa/ 3nAbjYeh0/r27/2S1/vOA3/Deh9AUXe7CnaLS1r9P3nAd/8AlH2/pkXvVKWUlzdBo7IyrfwQRqKN Np06JJqnjxpgPStvDaxKwt0RFZizcsAAt2k07cA7gFgPJ3xbsOlZfiJucm6bjulve85+TDaJeGKl PUMMTrX7VD58BTrXb/h8YYzLue9g6shGu5FdeXaYOOAI9z+GYVdV9vRAbiw3TNsuPssBrdWfwtKS c293dRzKuSNy9OhyziOAtfw7tujl+ImzPt93ub3/AL1FSK4F9yKVHHmxrHw4VOA9LbRabYtyz7de 69P7+OJYdLcaatCA+bPAce+bJXbbuluW4SX32flk/a5Q8h+vAefNzi3f8NHvkyG11DgErWv6q6sB ty9293PtYNGg+kIq0p5VrX68BG2Ud9yB7tLBy6mnMEfHt/eCuA7T8rUFq991cL64SJdNmZWQIVyM 9R4lZKEV4YD0xs8VlHasLKZZoC7EFAgUE+r7MKMvLngDsB//2Q== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/__chars/less/special/les/black/med/base/glyph.gif R0lGODlhCwAMAJH/AMDAwDMzMwAAAAAAACH5BAEAAAAALAAAAAALAAwAQAIVhI8om8cNRQsP2puo VOFuQ1lLhxkFADs= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/journal/v94/n3/thumbs/6602935f7th.jpg /9j/4AAQSkZJRgABAgAAZABkAAD/7AARRHVja3kAAQAEAAAAPAAA/+4ADkFkb2JlAGTAAAAAAf/b AIQABgQEBAUEBgUFBgkGBQYJCwgGBggLDAoKCwoKDBAMDAwMDAwQDA4PEA8ODBMTFBQTExwbGxsc Hx8fHx8fHx8fHwEHBwcNDA0YEBAYGhURFRofHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8f Hx8fHx8fHx8fHx8fHx8fHx8f/8AAEQgAlgBmAwERAAIRAQMRAf/EAIEAAAAHAQEBAAAAAAAAAAAA AAACAwQFBwgGAQkBAQAAAAAAAAAAAAAAAAAAAAAQAAIBAgUCAwYDBQYEBwEAAAECAxEEACESBQYT BzFBIlFhMiMUFUIWCHGBoVIkkbFikjPUctJDJYOjVGR0hScYEQEAAAAAAAAAAAAAAAAAAAAA/9oA DAMBAAIRAxEAPwDStlG+3wta2tq7Qxu7VknDtWRy5YlizUJYkVwDe6m3tn60Ewggc5K3RceFPS1V 8/bXAEjfkiuUmuEL6fgVYlIPjXNjkBgHdtfX0dspnRZiCQZxJEik1qBQEjwwHv11026WULL0Uljn Z4iytq0dPSwIr/McB7uWwWG4ydS4MgJABCNpBpWhNPP1YA322G1u59xtYtd3PHFDLrlZU6cNdPkw FNR8BgBcy38kPTpDCZqCORLghq+I01iIOAjjByAOy/dEBQFnUtDUL7/kZUwCsR3WMQzSX0ckS5Nq ljCSEVrmIR/A4B+Ly76yxNHBrJGpFnJcKfEhTGK0GeAQ2+u5bTNHcOzCWS4iLqQGCiV0FCPYBgEY +KWKW0luJ5zHKukksmoCqnI6PYgGAxHd/qF70LeXfT5PHGGmaMq0FkGKq5RdVYfAD2+WAWTvH3fl lh2xuY7YluI+tHrSy6CHURp1C3ID+dMAme93eI2cm8Ny+xa41mBounZ/VMurpkhOhmlM618MA8j7 pd3Wni2n837OYJY/qlq22i3DfDRnMWlZKfhOeAmeA97+597zzjW37hvi3kcm4rZXCpFaaZIDMFZE dI1orhR6gffgNa7fyWO7lRHiji1sUJ+ohejZUWitUnPwGArv9TnMeScU4JY3+wX7bfdzblHbyzKs baomhlYoeorrQlRgMxr377rydMNyZqQlTCGjtBpPgCtYsqYB7D3i7uXMZu/zTDqnCRSGR9vWQrIw QB1ZA2n+avgMzlgHp7hd45JU24cpsGQJ140NztPRFWK5MRoD1PhWvngCJ3S7zpXd5eVWzLBKYpys +2G4ZY5OmyogHVYHy0jMZjAaC7S8/wBzvdkuprm4iu41uVRTK4i6ZeNXZVCRnUSzEn3+eAsyLfFk sJrheiZoXEbxiWqhmYKAz6cjU+FMB8/7+/4mbie4PCpGhaeVBP8AcLnSzI9GodPvGAfRbHaS3i2S dtr1rx0aRLcXd71CiEBmC9OtASKnAEXa9sNmt6O3lybNnMQuPrbvR1FcRldXTpUOdNPbgJOLhzvu Mm3jtvdC9iiEzwNuFyrCNjpDHUoyrlgJrt3Bxe25jxW6/LbWkn3SBNTbhcSiFxMVZumVo+kp4eeA 2Rabjx65kiS3EZdmrCOiynUBWo1KKZYCrf1Vvtq8B24bhtq7pE+6xKls0ssNHME1GDQkMfZTAZZj HEn6mnhsZEWclL2+On/i9WWAcxbdx2X6bp8H1/WHTaEXd+eqa0pH6vV+7AOYOO7PMbkR8DLfR0N1 /V3o6dQSNdWy8DgDy8f4/aR2l1dcMjgt7rS1vMdwuiWDLqUgCQtmB7MBob9OG67Pa8f3hLfbZLRT fgaYmuLyp+njOpmkLlPH9mAuZNztGtJLpUkEaMFYdJw5NQPgpqPj40wHzvudm4LNfTsvJLxS80h0 naxkS5/93gHsOycURww5ReBlGR+3EGnnQ/V4ANsHEWQD8y3YWuQ+25Vr/wDLwCn5f4q0jN+ZbouR Rq7bWv7/AKvAdX222rZY+d8YSPkt9PbQ7lbGC0ewMcRYSDLqfUME9R+LSaYDY0e2bJK3RivZHlPq 0pdyF8hSoAfAVt+p+02WbgO3RbrdXNrbruUXTktYUuZC4glABWSWAUpXPV+7AZlTZ+3+dN53b3/9 ut/95gFRs/A6KPvW7UHh/wBut/8AeYA32jgQJrvG6n/663/3mAPHtHBS69Pdt26h+HTt1vq/heYD QP6d9q4sOM7vGLm4uYvrwXO4RrZsGMEYoqpNLqFKZk4C3k23YVie6XQIH+OXqtoNHDeOrT8QH92A yjJ2Z/UUy2EH2rbmt9qlEliK7aGBQnQXbRqky8dZNfPAP17WfqOXcLu/+1bY1xeRLBNqXaymhK00 oUKr8XiBn54BonZbv2Npt9sbY9rNtbydVGJ28ylg/Uo01Oow1eRbwy8MA9btF3zfdrncpOM7K8tz F0WiKbf0ANQbUsQoobL4vGmA67g3bPubt0O02m5bXDbQQ7iLq7MM8BSONpxI3TjUkUA8FGAu622E W7RvHdza0ctI5WLVID+FiEGX7MBxfffhvKOVcXsLPjdvb3N/a7gly8V2yLF01hlQ1DhlbNxlTAUX H2C72oZSNs2r51NVZLY00inprH6f3YAw7Cd7ALcfbNqpbadHzLb1aRT1/L9fv1VwBz2H72FZR9s2 r52nV8y2y0ggafl+nxzp44Ba17E95ojbBts21FtmDLJHNCkpoCPVIqhj4+eAt7tL285NtG27jHyT Taz3F4s8UcEkc4eNYUSjllanqTAWJHtGi2ltzcO8UjqyqUioihtRQAJpofDMVwEhgBgBgIySG3gn vVEV1IbyjTMmqg9GikbVBXIeWAjbyzuREiWMd4QurUJpp1OdKAMrnIZ+OAbra7yxKSQTdJmGthc3 RbSB+H1ZYB7bWxAaS4ivRcSEaulJKEy8KAvl78A+u91kSNDHDJGxmgjPVSgKyyBDQ1pWmAU3XaU3 ARBriaDpEkdFtOqop6vGuAcWdqLaERB2kzqXc1JwC2AGAGAGAGAGAzR3f/UDz3ifcfdNk2qCxksr BIVheeGV3pPDHK+orKqn1HLLAcev6oe65IYWe2j5QQVhmHoY5eM4/twElH34713ENyV27bCkdpqn 8QRbqH9Q/qq1ybMer+GAeXHdvvzJcXMTbTtjSm2W7nWJqnoRlqONF3/gNdOftwDK476d17F1m5Bt lnZw3oW+s5DDOVleFlKlPnSDSNQqBgNH8U5g+6cd2m+u7ac3d5ZW1xO0MD9IyTRI7dP4sqvgOnU1 APhXOhwAwAwAwAwAwAwGO+/238Pm7r72+4S7wt2wtustmLUwZW0YGnqEP4UrXzwFeDj/AG9b/q7/ AP5bH/mwBxxvt+PCbfv8lj/zYAy8e4Epqs+/g0IyWx8P82Acbfwrgu53CWiXW+q1GK61tNIAzPwF j/DAbG4ZtfEk4nssVY3ePbbWEtPIon0LCijqBW9JyFaeeA7G3ihigSOEARKoEYBqKeWeAPgBgBgB gBgBgMj99Nrhm7pbzId82izZjbMbe7acTLS2jFG0QSLQ0qPVgOLj22EBQeRcfIVtXjdZn2H+n8Pd gH8ItYjERu3GZOk5k9YvDqqKaXpCKqPIYBxDfQQ9MruHEnMbvINaXbA69XpasOarq9I9wwC22X1s LmIzbnxwxQmWSlk11bTHqVyaVbZm0LqyH7MBp7i3HIbjjG0zpdqyy2NuVaOOKSNgYUAYNJHrcZVG r+zAddbxtFAkbOZGRQC5ABNPOgywB8AMAMAMAMAMBlPvTxLeL3uXvV3DxLcN1jle1aO/gW46TIlv EGRemhU/Cy6q/wB2A4wcL39SdPb7cqdUOAyXxolBWPJR/m8cAYcQ5EGX/wDPb4gSMxHS3DNCDRPH wWoz8csAVeH8iBj19vdwcKXLgR366wx9I86afd44BM8D5NLHEsXC9ztJERhNKbe6lEhNKel1ov7s Bqzh/Fr0cU2b6nRFNFt1oi200MgeKVIUBEg1rmCtKUFMB2kAmEKCZg8oA1so0gn3CppgD4AYAYCM sL+SG36W4XH1F0juHkihkC/EaDIEZDLAEut4ukk/pYUmiNPj60bA+f8A0nBGARj3zc2aj2caLRvV rmbw+HIQ+eAd227hoybpDHJUgLGsrjT5GpjT+7AOFuluYpltXImVaKXVloxB0mjDwrgEbCPexcSN fSQNAR8tIg1Qa+ZIHlgDl7m3urm4uriMbeVjEEenSyNmH1N+LUStMAG3fbqHTcJXyqcq4CMbkt2u X0Ub0oNS3KUNfMVAOWAUXkUxQMbWNW1EFTcLXSMg3w+fswEh9223/wBQmASv13G6ggk2q7jhBOpn ZBIroRkB7MAdYd0Fi6NOhvD8Eun0gZDwp+0/twHHrzPfJDHPogWin5YEmk6qHMa8yKZYBI8m3rpT RGRPnMX1gyakrnpQ68l92AKeTb2ZLd+qo6AC6KyaXp5yDV6icAX8xb1/UHrj+o98ny86/L9Xp9mA m+M8hv57tLG7aNohC7iY6tZKsoGpmYg114DqldW+Eg/sNcBE8k3i62y3ge2jjkeWTQeqSAAFLfh/ ZgOWl5Xvz2xgHSRi1ROrPr+LVTwpTy/ZgPJuX749xFMoiRY/GFWfQ/8AxVFcAkOVb/W5PUQ/UAhR qakVSc4/T5e/AFflO/tbwwiVVaIktKGbW9TWjemmXuGA7PjW73G6WD3E8aRyJK0ZEZJUgAGuefng JXAU49tHMIXaeWJkC+iNyoNB+IeeAip+KxyRyRje90jLsra1uvUumuS+k0BrngCXXE452tz983SM QKFIS6K66GtXouZwCE/B7Sa/e6fed1zFFhW9kWNamtQowHW8M2BGnG3dd7hAksolu/6lv9SMgHX/ AArgO+sNkuLGVWhuY1j9ImRYFUuFFPiBywDDnRAs7SraQZWGo0y+W3twFczbXfvA0a7/ADJIStJQ luSKVqKaKequAhLziPJpblJYea3cEaqoeEQ2rBiooWroy1YBknCeaAFX59dkVBWlvagintNDgDNx bmsd/aSrzed7eNl+ohe2tgJFVqkelfxDI4C2OObTcXtmJ4GQJHO6sWkmX+U5LGQp/acB0cdju/26 W0kMHgohZZJ6/FVtTk6/DwIOApjc+6Gw2O92+03W7vFuEix/IM0tSZBlXOlTgIp+8PGpLOeaLfyY 4WQO63Unp1Egfi86YA6d2thL2Q++H+oCmIfVP66uV/nzzFMA3fvDsKi9P3xj9OPm0uZDo+YE/m9p pgO97V862/eJhdwX0t3adGUM4aWerCSNfh9R9NfGmAta2uYrmFZotWhvDUrIf8rAHAVx3+5BebFx G1vra+l28C7Amnidozo6UhoSvlUDAZ8PeXchB1/zRd9LWE1fUSn1EVp44A7d4tzEsEX5mvNc4QxL 9RL6g5ov9uAMO8G5sZ1HJ7ysClpT15qKFYKf4nAEPeW/SCOZuUXnSkdkV+vNQlQCR+7VgNCdmuWv uPCLa8u7i53B7ieXpXOmWeqagANdG8MBZNRStcvGuAzluf6d+bXu7LuLS7U0qEFJGeUuApyz6J8M BFT/AKWOWS20sAbaFWUqzgPKK6CSK0h9+ASX9KXLA9qxfadVqAIvmTZUcuKfJ9pwAH6UeWgXID7R /Vf6nzJs/WHz+T7RgLF7R9mt74jeSrurWb7c1u8SQ2kkteo8qPU1SPKinzwFrW+0bfb3H1EMZWWh BOtyM/cWIwHBd+O33JOc8TtNp2Ca2huor1LiU3buiGJY5FIBRJDXU48sBRa/pT7rhdJutmIrqp1Z vH2/6GAWH6XO7AKsbnZqrQA9WbIDwp8jALf/AMyd2aMPqto9Xj86bP8A8jAeD9MPdfTpN1tFPGnW m8//AAMBeHaXtzeca4XBtHIktrjcIpp3D2zO0YjlaoUErGfDxywHbJtG2pavaLABbyMHeOpoSCD7 f8IwCNvDJYLHt9nFEsChjAJJZC7AEF2JKt+J/bgCz3d7LBOEaGIwZySrI5KaDU+MdD4YCOEu8GF5 xuyGFH6bNpWgeuY/0ffgH67hd26RRTPDJIwSkjO4LazRSQsVBU4B1Hd3Ru1t5EhBIJYK7lgoAzAK AHMjzwEabbaH3TqpLcy3MUrHooH6YcVcj4Qv4vbngJF9vWO8nv7epvJkSJlkdulpQ1rpFaHM+AwC Rvb8Q9YiHp6tFaTV1atHw6a/F54Bjftf9ZWa8a3aULpSISMueQNDG9Pf/HAHto90hvek14Z5EBPS k1aKUHiyxqD4+3AOoNwvpw5iEREahmqsy5MKilVFfDywBbye2utqMV9I0C3LmIPb9QNqD0Gk6dQ+ H2YBpFtm3LtM5696baQL81geqAH1ehdGrMjP04Cizd771Gq11TUczJPXANxd8o0SEiYPT5a9a4IJ r+LL2YAn1fLOiKLIJS3qXq3OnTTyNPGuAaXt7ztbmP6RS1vpUymSa8Dhq+rSFFKU8K4BbZb7nb7y q3Y07f1qI6yXfW0avTUN6a+3AaCjvOQpNIZFnliSTJRbxLqWpFFPUr4eeAhe6t5u35YtbjbYrhbp p6iBWeJ/9N6K7R6qCuAqK43Tny22uK1vDc1AMf1VzpC0zOqnkcA2fd+4ghjK2d60rKeqv1dyArVy odOeWAUO6c8+o0fTX/01f9b6q51Up/Jp9vvwCMW7dyGikaSyvVmUDpILy6IY1zqSuWWA77tbfc0k XcJL2O6t7gCMCJjJeDTV816pjAPtwFkpuG8iKSJ4ZzOwDRSiBQop6ipHUzNMq+3AUjFabol2xYwi 2qaRmMa/d6tXt92AWEN4IXDdAykehggCg19mrANrq03dokFrJbxzBqyM8QcFaeAUOtM8AjJZciM0 LR3FqsKoBcKbepd65lT1BpBHlngHFrZb994WRri3O3mQabYW69QDKg6uv2/4cBdItuRpLIwNw6CQ MgaeCjLqOVOn6RT9/vwHvJ9xgt9st59wmi21pGKK8+mREkKkgexjQHAcXuu82VxYpFY8psLS6WXW 1ybaOQGPTTRoLKPHOtcBH3t/PIlkLbmW3QtDEEvGayjfrSBiS6jqDR6SBTPAe/cW/NDXo5Xt32Uy Fhtptl1hNFAvV1/zZ104CNs7neILHdEn5Zs9xczwqtg/0xRYpBIGJejtUFKj9uA6bgP3u7265gm3 O03Dco5OoZNsdrZRCwAVXLLIfENgOyjtuQJHLEVZ+qFIlN0NSMorRfl+DHI4DJW97bvMvIvqId4N tZh1Is1ty4IHiDJ4erARzbTvA+qMm+uyOrBB9MR0yWFGH8xHlgGT7RvH0BQ7/cl+qGEwtn1fDTTp C1p51wHlxtO8FLYffLpdKAEi3Y6/UTU+nL9+Ak9p2/dl5PaTtutzJCJ0JtGhIiIqMtenTTAa/tBu 6XczW4MjEvRLl7oR6dXkXjCVr7PLwywFffqfjlk7fWqLIIJmvABIAW0noS5gAEnAZU+2bn9jlQ7y 5YzIer0J6gBT6aBddDgFLna9wa121RvMiaI2DOIJiX9ZNSNNR7PVgHo2+8/MvW+6P065WvRk0fBT 4tOj3+OAa222bitrfh94kcvHRGMEo0esGo9OfsywF0fpstLuGHfkuL57pybcrL07lGUfMypEFelP 3YDQSLuH2uQO8Zs9A6RAuusF1CurPq10199cB//Z ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/jpeg Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/journal/v94/n3/thumbs/6602935f8th.jpg /9j/4AAQSkZJRgABAgAAZABkAAD/7AARRHVja3kAAQAEAAAAPAAA/+4ADkFkb2JlAGTAAAAAAf/b AIQABgQEBAUEBgUFBgkGBQYJCwgGBggLDAoKCwoKDBAMDAwMDAwQDA4PEA8ODBMTFBQTExwbGxsc Hx8fHx8fHx8fHwEHBwcNDA0YEBAYGhURFRofHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8fHx8f Hx8fHx8fHx8fHx8fHx8fHx8f/8AAEQgAlgBSAwERAAIRAQMRAf/EAI4AAAIDAQEBAQAAAAAAAAAA AAUHAwQGAgABCAEBAAAAAAAAAAAAAAAAAAAAABAAAgECBAMDBQoICQ0BAAAAAQIDEQQAEgUGITET QRQHUWEiMhVxgZGh0VIjMxYIsUJiklPTVNRygkNjg5MkNITh8dJzo8NEdJS0xCUXVREBAAAAAAAA AAAAAAAAAAAAAP/aAAwDAQACEQMRAD8A/RcW17OztMvtK8RUmmuGnacK2a4bNICcoGXPxA7K8MAM vV6U0scFze3EVDkZL6JQa+kfXp/B7cBPptrbygmfULy1ZCERJL2Nyy8/xK8K8MBorq9trZG6kih1 UssZZQzU8gJHPABW3Ve849MDCnqtdQK1ezm1Ofn4YA5b3ltcD6KRGegLIrKxWvlyk4Abd6+8N4sU MCXFuaZ51uIky1ND6LEVp7uAqpufUjIivp0QUsFkZbyEhQQCW40zU48sBoI5I5EDxsHQ8mUgg++M B1gPYDL733toO2xaQ6vbT3K3pZ4khRHFYGRqtndO1hTAZn/7RsdQc2mXR7RS3gHD+tOAgl8adhSZ 0k026a3dCjx93gqa8D6XV8mAlk8a9jySNMdNvGmYKpd4IWOVSaDjL5zgOX8cNhJ62l3g7P7vB+sw Edt45bFjdZPZ953lUKGVLeFKqxBIoJj80YD7H417BjVUTS7sRIoVV7vBwpwHHq4D0njhsU5cmm3a 0YFq20BqvaPrRTAG9sb80rdEN3ZbaEumTWlJpHu4oxH9Mzk5Qrvxz1J5YDZ2bSd3RZpVlnApI6kU J94D8GAnwCb+8L1RLoBjVmoLquUE/ofJgFAXuyD9G/L5jfJgADbX1NiT3u4HpVplbtNacsAc6V1w 9GTgAPVbs97AUdZ0/UL206ETSwvmDdRVavDs5YClpOiarZ3JlmnmnUqVyMrcz28sASS2vhz6p49q N8mA5mt9QaYunURaUy5DT8GAZXgnpdzeHWoJLUXTdO1YLPnjUkPJxqCp4V5VwDbttD1S1MM0GmWY miLZR1paIKhlCglgKtzPZ5DgCvetz/sMHq1+t/H+by5ef4sAv/HTWtW02TRe4XlxaiUXPUW3meHP lMVM2UitKnngFU+891E09r6gg+d3uU/gfABn8Sd+gEdXVagkVGoH/TwF4763cjge1dTkBAOYXkgA Pk4vgIbzxA3hFb9WPVNUkeoHQW8kzU8tS9MBXtfEfelxcCN9Q1a3QgkyPeOV9z0ZCcBZG/d48R7U 1Q04A99fj5/rMBY+2+61NPbOpSCnMXco/C+AYfhBuvclxLq8ktxNfmOO3yw390ciBmkDMGdmUchy wDRttw6g0sAnt7ZIpHySTLcxsFNewVq3Dj8VO3AGu+2f6eP89flwC98Xtqybgl0sRyGNrRJ2Y1QC jmIfjdtRgF4nhLfTMVS4JNK+tFyHv4Cs3hVcE0M7/DF8uAjn8KpYbhbd7p+qwzBc0XL4cBy3hNKI +o1y+WuXiYufw4D0XhJJK+VLp83H8aHs9/ARf/LyP+Kkr7sPy4CzN4TzwOFe5epGb1ouXw4DdeFW zLLR7nUvaLLNDdxwqqT9MpVHYU4Hmc/AYBkRaNtu4jAitbaWNcwqgVgM/rCo+dTjgO/s5of7HH6u TkfV+b7mAzniXtS13VpraJdajPpUVxHnF7bNklVopo3yhj86nHAY3Yfg9a7S1e6v/tfeanHcWktp Ha3TgpG0uWko4+suXhgMdb/d33HFcxSSeJN3KiOrMlGAYBgSPrTzwGk8QvBo7p3Ydett2XOlqIUg itbYjKoUekR6Q4tgPT+Dwm8PRtSbdN28/fe+HVQwFwRxAj5+rgK2w/BC32xrp1OTdN9qSd3lgFtc SUQGUZc448wOWAxk33eN6Bibff8AcAVIAYS+rXgOEuA1/iX4W7t3BrVpf6Bu06RHBZRW0luAzK8k ZYmQlWA9LN5MBovCzZO6tK0e70zXdVt9dv5JDNHczxs8aReiqqVNPSqpIwG9t9K3BZAixNjCjBS6 LEyZnoMxOUcTWtD8WAP/AEvlHq+f1vkwAHTta3PLZrNeaEY5jNLG0KTJURrTpv6XPNUj3sBK2vaq rOnshi8Yqw7xBwqaCtTUV58uWA+x61rLkD2M/wCVSeE0PvHlgDVeFTwwELXtmrlGnjVwKlS6ggc6 0rgJsBHJc20TqkkqI7+qrMAT7gOA5W9s2kMSzxtKDQoHUtWtKUrgJsB7AewEV2t00BW1dI5iVo8i llAzDN6IIqctaceeADXO3GvZGluXt5nJIYyWzcTTLWhlpyHPAdW+k31iJYdPmt4XdepQWrrGzAZR mYSH/NgLt/b6jM0ipPHFaOgQp0mlclqhqkMtBQjACjsy2KBGW0ZByVrZmHn5ynnTj5cAV0+PUVKG SZJLUxkKnRaGRWBAXgzNwpXngKNzoVzftGdQktppkUHjbMyKfySZByPLtwHCbc7rOLiI26TOwBeO 0YmubOC1JOxuNTgCE19Np2n9fUKzyKzKTbRsagschyVJrlpXjzwFqzukurZLhFZUkFQrUB5040Jw E2AS/wB5O6mt7TbpjleMGe4zBGZa0jXnlIwCVbWZ8tBPNX/WP8uAC3G9L2KR41Fy2Q0qHkofjwF6 LcN00SOZp6uoOXqPw+PAV7/ct/DbPPHJcO60AjEj1PH3cBRsd46tdXKwyrcwggkuZJKcPfwBFtwX WWnXnH9LJ8uAoT7rvYJmjD3LgCuYSSEcffwDU+71uDU31vV7qFjM4sY/obuYpGAbhQTVzQEDAP60 3BfO8feUtEhLFZJUuUIBDKKLzLeiSeynAefAGPaOn/tMX56/LgFV94WDS57XQUvormRutOYe6yxx UpGubN1I5q+alMAmm0rbdONtqY/xNt+7YCk1vtMMV7nqta0/vNt+7YCb2VtYiottU966tv3XAQXF ntOFMzWmqnsoLq1/dsBFDFtCZios9WWg5m6tR/42Al9mbTYf3TVR/irX91wFSaHZscjKbLVzTtF1 a0/7bANDwHi2bBrmqOY7mGN7KPqNqE8EkVOsuUAJFCQ1fPgHhEuz5liSNbNxIT0QAhzFsqNl8tSV U4Cx9mdv/sEPLL6g9X5vuebALzx407UbyLQjZ2dxdrHLcdXu0byFcyJSuQGlaYBUNoWv1DLo+oVH IG2nI+DJgM/J4aag7tIdK1nMzFiAl0BUmvLLgC/2e3EQK6NqIoKCltcDgP4mApajs7Xb6A28ujam IswaqwXKtUflBa4Cnp+wdZsJjLb6JqpZlKN1IbpxQ+QMuAJJtjXkVcuianUcq29weX8XACb7w21G 9uJLmfRdWEspBYRxXSLwFOQWmAZ3gltPWoNW1C3ksJrKEWCRwzahbSNHmWVSPrQuduFeeAcQ25qi hHWe0FwkhkEotUBHLLQjlQ1r5fNgLPdd3ft1ry/Qtz8vPl5vjwC+8f2YR6AAxAMtzWhpyRMAiRvj QuqIA0plMnT5NSuamA61PeWl6devaTCVpEAJKgkcRXAfbnd9jb2FpemKZ4ruuRVBqKeXAd2e7bW5 sbu8S3nC2lCY2BzNXyDAd6TvG21G9S1S0uIi4JDurBeArzwH074t1laHuF0SrmMsEYjgaVwFvV9y +z7k24sbiciNXDxozA5uyowG98IdRu1u7rUlZrEy2IYdaJ5aUnQspjWjVIFPNgG1Zbogtsw1O9Ex cB42jt3jCqTQBvWzV8o9/AaDvUPl/k+ryPqeXAZzc+2dsbuW073ekizeUQm2lj4sQqyKah65aD3M AAHgpsMVcXFxw4lupBzHP+SwHj4L7Edqm5uGYitTJATTy/VcsBOPBLaAAHVu6DkM0NB/ssB2vgvt NeU13+dD+qwHa+Dm1l9Wa6/Oh/VYCZfCfbi8p7n4Yf1WAmXwz0NeVxce/wBD9VgCei7R07Sb03kE sskpiMNJOnlCsyseCInGqjAG6DAepgA0+g7bs7BI5rRTaQPWFGEkxRpSECxj02APBQq8MAEvdNsW uJGtNOt+kwonWs7uo/GPBIxzfz8sBNZWWgwRSS6jp8SCM5laG0ulRUAzMWzpw48cBobzVLe3MkCB 3uVjDqiRSyKM1QmYxq1KlcADfVdzN6SNChIpkNpesoPlB6YPD4/NgD1pqdtcSCD01uMnUKPFLGCA QGKmRUrQsMAKuNZv5LqKawcGwYKxD2t0zMDzKssdOI5HjgOLfU9ZEsbTzB0qvWjWyuxw4Z8hyfBX AHrW7guoRNAxaMll4qyEMjFWBVgGBDAjiMBLgPYDB+KviBqez4NLawtYLpr6WRH7wXAURqGBGT3c Bh18dt1BCw0+w48aF5zz91sBC3j5uYOXbT9PzUylDJPlpz9XNSvnwHweP26pKgaZp/GnEPMOXLiD gPkv3hN2R+tpmn0HM55vlwESfeE3Oiqi6bp7ECgrJOzU85LE4CUfeA3WBnGl6fwFKZ5qU9ytMBE/ 3hd0MVD6bYKVIYfSzry8tG4jzYA7s7xan3Ze3mm69DDptjDB3hbqxeXOZDKsYXk3A5ya4Bl6Vreh dK3tLa6aQsCIg6sHb0gpr6K/jNTAGcAqPH3Q9X1W00T2dbG5MM05lCtGuUMigeuyeTswCjXZW7QB /wCtk4fzsH6zAD7rwy3HNI8jaXMWc1b6eEf73AdrsHeKRrGmmS5VFB9NByH9LgIbrw83jcQPC+ly 5H50ngB+Hq4CpaeFe6rWdZ4tMn6iigzXEBHHzGXAXTsDehB/9ZKK/wA9b/rcBRvvCzdd5N1ZtLmz AZRluIFFB/S4BleA+xNyaXrl/HcxS6fAbEpHcs8UrZuvG2UBHY8hzwDuGgagIwo1ecPmLs+VamoA Hn9GnDj7tcB89i65/wDuS/1UfP53+TlgFz94rL3LQsygjrT8/wCCmAUcSRZAAkdPLQYCtcJWQdNI stONRxr72A+RxjLRkjLg+SgpgIruFuhLkhiMxX6Mdhb8rADbO11BZ1N1bWyQ0OYxmrVpwpUYAj0Y iv1SfAMAOvLe6zube1hlThQuaHlgGF4KGeHcF88MjWc40703tohO/CeIsip21wDrh1a/i6Er3t5L CspWRGswGdVKsakGg9HgKc+PCuAL/a7SvmXHLN9RJy+Dn5ueAy/i9p9hfQaXHeQRzKjzOrStMuWi rWnSki5+euAW8mh7ajCgQWuZzQL1LvjX/E4CnPY7WhziSC0VozQqZbsf+TgK8kW14umXt7NVlGZS ZbsVH/U4CrLPtdUeU21l0UYK0nVvKAk9v9pwEkR2lO+SG3spTlLELLeHgOfK5wHxG2g6rSCxLsQA gmu+ZP8AzOAkMG1VeSOS1s0ZCKqZbwHiO0d5wG28JJtvadrOoX0dtDAotUQ3EBuZDlkmUUKySzCl VBJA4UwDg07VrLUVka1ZmERyvmR0of4wFeWAt4BbeNZpp+n5hWOs/U/g5FrgETH9mxdW/QyG4zDu 49LNn7KVOAqaz9mO9zd/6Pes30/U9atO3AcXp0bu1r1xCIsn9kz0oU/Jr2YCg/sg2U4HRFlnHVPD IW7M3nwE2ljSRJ/YDCZchr0stcvbWnZgOIPs9nTpd2z5hky5fWrwp58BNqHsnvEvehCLj+Vz0zUp 2+9gGn4FxCW71NEmlt7c2cfSktQWcL1PxMqsfiwDdk09GZMup6kj5BkpHIRQczxj7e2uAO5D+kf6 rLyP53L1sB//2Q== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/journal/v94/n3/thumbs/6602935f9ath.gif R0lGODlhiACWAPcAAAAAAAEBAQICAgMDAwQEBAUFBQYGBgcHBwgICAkJCQoKCgsLCwwMDA0NDQ4O Dg8PDxAQEBERERISEhMTExQUFBUVFRYWFhcXFxgYGBkZGRoaGhsbGxwcHB0dHR4eHh8fHyAgICEh ISIiIiMjIyQkJCUlJSYmJicnJygoKCkpKSoqKisrKywsLC0tLS4uLi8vLzAwMDExMTIyMjMzMzQ0 NDU1NTY2Njc3Nzg4ODk5OTo6Ojs7Ozw8PD09PT4+Pj8/P0BAQEFBQUJCQkNDQ0REREVFRUZGRkdH R0hISElJSUpKSktLS0xMTE1NTU5OTk9PT1BQUFFRUVJSUlNTU1RUVFVVVVZWVldXV1hYWFlZWVpa WltbW1xcXF1dXV5eXl9fX2BgYGFhYWJiYmNjY2RkZGVlZWZmZmdnZ2hoaGlpaWpqamtra2xsbG1t bW5ubm9vb3BwcHFxcXJycnNzc3R0dHV1dXZ2dnd3d3h4eHl5eXp6ent7e3x8fH19fX5+fn9/f4CA gIGBgYKCgoODg4SEhIWFhYaGhoeHh4iIiImJiYqKiouLi4yMjI2NjY6Ojo+Pj5CQkJGRkZKSkpOT k5SUlJWVlZaWlpeXl5iYmJmZmZqampubm5ycnJ2dnZ6enp+fn6CgoKGhoaKioqOjo6SkpKWlpaam pqenp6ioqKmpqaqqqqurq6ysrK2tra6urq+vr7CwsLGxsbKysrOzs7S0tLW1tba2tre3t7i4uLm5 ubq6uru7u7y8vL29vb6+vr+/v8DAwMHBwcLCwsPDw8TExMXFxcbGxsfHx8jIyMnJycrKysvLy8zM zM3Nzc7Ozs/Pz9DQ0NHR0dLS0tPT09TU1NXV1dbW1tfX19jY2NnZ2dra2tvb29zc3N3d3d7e3t/f 3+Dg4OHh4eLi4uPj4+Tk5OXl5ebm5ufn5+jo6Onp6erq6uvr6+zs7O3t7e7u7u/v7/Dw8PHx8fLy 8vPz8/T09PX19fb29vf39/j4+Pn5+fr6+vv7+/z8/P39/f7+/v///yH5BAAAAAAALAAAAACIAJYA AAj/AP8JvGZPoMGDCBMqXMiwIUN+CakRg5hQHC5q45jtW1hPHTt28NydG/ft3jl/6KRRw+ZO2792 4Ljhc4gQ3xlhDs9hSzdP2j2aQIMmZGfM5UFLatgpfMcM2zpW4BZ2+2YO3DNQopDFCpfsH6INJGhw U1ZtljBb4YT+Q8fKmENho55l0wSPJr1y6M6tK+ftGzV44faR09Xr17pp+s5loxavYTd6v0yhM8gL FD2HybotnIdOXTp55c6Js8ev3j9xyJQ5y3cPX7t65PKpDdoPn75/zdzR/JatXDhppTYlg/VtWb9P FkSQmCbNWitkuLA1/OYPEABJs4tpns29e8J24+Dp/wP2jmY+d+/e3YsXL53smfLCjRunb5+/evna 3WZIPdD17Nt5JyB3zpziTDSTzDPggv0BMElD7Oh2kDEBLtgQOcC0M+A98JimjIQWdtfggwv5k8sw /hikziNRhciQP8V880x31CjzjzzsKIgMiC6qNeJDs3BzkD/DVNjjkM7808km66jlDyzN/MMMKc1Y o4k8QG10pEA/ljiMUQZpt2VC/kQJBACrZDfNP/GYEw+MPC6UDjDVjNmlQvzMAqZAYo45ZJRFANCK k7ZII5A9M+1IUzTsSNPPlncq5MuMBzFj5Jhl/hPooGoBE80/0JAi15U0UdMONY8eGWlCyFDzTznC ZP/jDSYt+ilQppvOxosvN4KTjj/GxKmQqdSkqKo//pG4kDbn/AMPMtmcQ8o3thqEq6CzkVOOQP1A lFup7UgHqT+CAOBIQ7Ywg5Ayl255LadCAWPjNKZAgw0nWDpEzTyxJFJriNT1AcAxDe2i7kF9Vvvu bMAU8w871JQjjy7l6csPHADwcqQ3/cRxh0O/1Dlhu1sCiq1avxCDECzb0DRNPnVQsuU5+BDTDTAN AXPNkMKQ/M85wKQzIDTwzJirWsjsbBA+u2zr0D38vCNLLH5qIQhD+axizUHmFJLWQr+gMwsx+QqF jzGLbPBFnUcH5c8tBPOTz0amqEOTgsok8Il39oj/k1BjsQAQCUP72JINQhQypLIaAcisVjfefAJA EFu3DZQ+r+z8DSvLbBNK2QxJs88cAKDSXT/MGDMOQt34s4eDDSEDDUIJJ6RyGQAwMps38cACgBGV nyyU7P+E48w27dBSl7774AHAKd3tI008e/6z6kH9HLM1wj6rbIa5u7vjyu/BwxsUMw4f9C3zzkPP nfTttHzQ9Qb1s02cljLk8PfnquWN+OTTlPCA0o9orG4dyODGO2yxvIZQo3nPi5402mEk+hkEF5/6 hzWw8Q1N/Esg5TgDJQjGv/CND3gCNB9QmrGza6ziGN4gRWPYF8H3ScMdmmHHMgpiQT4Z5RvXMMco /6iFEGEAIAX7A5//AIhCywFFGFHKhz4exQxhRQSC7pvNPqZBDyvMQRriaFkP+QELpRmEXQfRxzMq AQAaJLF/QvnfCcvnJF/USR/x0JEVEfLA9kWPiwuIwDT2sa1wIAt2JcJFlLh3EHRggxdtfKMJA+hE mszCLeegRTGyga9SYfGP9KBAB6bhDzaI4VPJesgtthemCqGjHMmI5D9KuMQ5plAt/bgFMv7BD3ak ox/BqskrZJGqf/SxhlrkoijXdAIA/OIfqVwIP2JhqJE1chzHkCUt48hEOqrlFukzSBUPAo5bIEAC BRHIMbOoli2GcpT/gEEBggFNRC5FFJMxyDog8f8vdGBTm0rkpi0r2ZB7nEI66wBGM8JxihkKZBvx iEAGfqLOT75PmfCUJz2jqRB/yEM21irSNbPpxlkGtCEo+Yc/xNHNW5rNGEKrhzOoQQ5UOPQf3YiH BDRQj3bwgx/XsGgy37kmjdZTWUGpHTv+WdJtNkQav9hDEVpxj4EO0DvrE0hOJeCBZmDDDDGAxT/8 eFGixnOeR82Or6BRikBI4xwklSRNooQEc/HDqipUC0zyQZ6DbLUDXSECAPZG1qEu86wbtWdQlqGT f+gATfZoRhuX8Q80/IcmdYoCACzxj1n8TjOBkoWAwgGMZyTIrzrtgI2UAIBQjBWZ7cRoUdHKUYf/ YKMas2pFKYyRgwIQAhebKAALNGEMKRRgDqN4xCQ80YtMkGISt9DEI/7giFAYIwjHFQYiCqADU/C2 AIcghjm6w4+ffAi1ElDtP1jr2sLORraITStQuIENdFzDGtSYRjayUY1pVEMb2KAGNfZbDWcwQxnM gAYzmqEMaEhDGstgRn6xwV//ZuMaE+Yvo8hrXnq4oxzTMMc47JGACpjMtXWA7aKAgQU+bEMfC6jA 1lIAgGH84w+XPcg8vuENcYjDGwLBhz3ugQ6KFrOY/1BQtdTCjV9kIxS2GEUlgJCGWeTiB0YgRTC6 UINIdIMQNXhEKDrhiViEIhOYWIUqPPEIUJAC/xOQ4EQpVIECI5zCFkHI8i6ekINN8EIPNxjEZQ5y jVa0YhWkYAUxglGMZexiFquLB5C5lC97TPphpvkHPuwmkHYouR/ooIinBTIPDQ0oPvvABz3usZF9 0CPT9hh0PjKt6nrQYx6vvjWuYz2Peti6Hum0B6wHfY95PGqKCMlHOvB4DnSggz3m8IiSl8ydcRhD GMIYhjHiwQ5z4PAYdhv1P+jRpH/cQ2gCSYeW0vkPe6RKHzPRtJagJpBUC6S8BmF3/Y6BDGIsYxjg KMg8zsEOcjSjSflQikA6VO91GOscptbHNoyVDnQ/bD/yyNc99qgQb/CiGb+QRS+CcYxmLAMYwP/Y 1jpmOA902yOfP7tNP+hhLHpQRMiHAik99oOPTOtj0P2Yh7EMwg9cFMMXuGiLMajxi2McozDb2se0 6xFvf+zHWYPmB8zl4dB5UOQeFP05UPhBjGPkIhm9yMY68vEOcpBDG8MY72woqmlj7QOkcxPK0A8S 63zg2qH9qIc+4EH3ju4dKEM/fJZ68Yxi7KIWy1AGNqDojGAIY7zwGHQ9KnYPU1+cl6gSCDYyjQ4i foPT7qBoPZbX+XuvA8kCkUYtVkELVmAwGd6gRjeGoYsmbd4g7ABp6ztN0eH/wx3p3Efo/8ENU5/j azS5xjWwgWFwyMMe++A2OLIBUmpzhxzM+Eb/NY7hDG7IhRvViEY1KtYjiqjUWrBfSD9igYtWuEIU vagFLZyRGlcgQzYM9w+/Z24gwg630UupEnwCQQ/LE4AKJBDqMGnysB38YA1I1hPjEBXswIDlQA7h EA7cUA7g8BP9oCUCqCX8wG77kCr8MG374H72kXPc4n4O4Q7ksB7xcH1YIg/vYA/L0w+JdyvFNHRD CH+3sjQUITfcEm+ahhDtoAvMwAzV8ArMoAuYIAu2oAqpsAq4MBn24HngoGT6wH7tkE71ID/H92np QBHioHAethAhGA7iwA3G4A3lIA7UoA3RgA3Y8AzS8A3WoAzbgigCIQ/oJnYCcQ6yEXTGUg4g/4Vz /6AOMyR4AtEeAqEPmdYP5XB4QOgPg4YOmeZ9evUMtpB2xLAt8sALwaAMw4ALwJAMtEAMwBAVq1aJ +ZQPZeOI/9APbyIQ4xBv9zBo6bA88wBS8HCL+dIP4rB3HNgY9qAP97B67dAO7NAO7pAi/HB1yGZu 5fYP29gPV7dzt9J92xiNDAGOgyaKY+IO1gAM2tAMrXANrtAJt0ALqPAJqHALl0EPnrcO8UYP5KBP xdeN4rA8/PBLAsEOmaYOAal32gBh8aBs70ANyaANjwKEQnhvTIgPxnJkdod3WoKRKpUqtWEQhXeJ vaaQ+TAN76AP9iAPvaYPiqeONPEMuBAL3/9ADK6ADcPQCtGwEe6gZPxYiULyUD9xkKmiDvGWDi0C DuXGDuk0DxIygfd2DfFHk7ayD3dHD8eGb1j5lWAZlmI5lgnBDyZ4ENlIg0t2lmS5ZPMgCm6RENqg Cs9gDsvgN0Myk2RyOaDQClf3D97QDdOwDtewOgQkkih1lUumDpZgIwnBDczADfFgDa5gEPTADeIQ Dt7gDL4QDbNoKt3wBnPQBgbGDtOgDL9QlAlxD5bQCYXnh+LFDJ6gbwtBDuIggjz5C9HgC+pAWZ4g BmfAB+LQDOiwDMJADOy3ZFThEPZwCwYRD7q3DdmwC6mADMZgDlYJDUWwBEJADOhADrxgDcP/4Cpw 2I331g+pcgvTxhDhAA7jQF+xsAvJQA3oAGSQ0ARSgAZtJ57YEAwc95XyYAsHkQ/4cA+p0n0NoZaz QQvrWSL6UB8GwZby15YHEaBtyaAUOiZwxYQC6JxBIQ+u4AoKxx3mQB0IgaEZeiTCUAv6kA7OMA71 AA6zIBSBo1jf9AtqiaIp6iLVYGPSkArLAA2cYApC8QoAkGOzETIJUQsNuiVnyQ3puGTMgBPCJhv5 gAtC4Ts2KhTCYCjnwI629gpReiT94Ay5AAtw8AnRYAuyEAZkgJe28gzEsHcWGhRailRqoQuGYg7e AAzjAAyUcJI9Ug/B0A9qAAAiYGPGcKTP/1Qt1eAKdCqgdnqkeCoUwUBPuwhS6mkr9eAWdAAALeAW i1pjS7YO4mIQdQoUd+od2MBKBqGjW9Kp//CpofoPo2pj1aINOFFeP6EPWDqpWxoU1ICGr9qkLiKr tCqqR4qrtlIW/0AO6fINs6AKWUqpCxEOlQAKN3UQv4ATJ2qsIYKsoKqspOqoM4oPcjgP3CBaC3EP vsALy7OqCnEIR6oyCvELOPOtnOqp42qry7pk1mCvBlEPHqoQxBAAAFAJAiGvCaEIRxpOCHEM1XQQ ttCk/VAXoMMd4lqrt7pk0EALCJGqCREMRzo4nWWtCuGwAACxByEMlCUQ5LBpqXAZ4OBrBP+KDMUQ BzFgCAKyseTKrJjSC0B7I5KqEEZ0HdgQC4iAsg37sAqxD6xAKcbEDr0wCfrQjqqwAjjwDJRFAwBA BD3Lrxz7r9VyDShyEATLEEd7CMVAD6jAtAihsix7K78wO9wiELhwD7t0C8s6Oz0AAE0QtrParx1b Ld0wo+sADVDaDexqtEd6CElSo5UqEHK7EM9AMCd6DzbCtwlQDDPyt4HrHT7rr+VqK9YwI1TrDNrQ Cqmgto8bJQyLEIzgtAnRD1WSELSguf/AuZ77D6AruMlKukO7JeKwJioFEb6qOK/7D7G7cNcgMCu7 ENvgNAeRu5sLAJ37uYALvIRLtqabCyH/W7QIUQ61sLzNaw+6MA13QLsJ0QuYW726y7vaG7rdMbqF ayvRILCFKL4GcQy+oAnmC7fttkuNwL4Ra7zwe73Z67vbK7pi+7NLZgwzWqH8KxC78A/FEMCIlAxH 0ATLkCSVqxC0QFnosFd5Er/Y27u/68CDO7al6yfQ4KH10BjJmxC8srawi7KhcKSssCYhjBD+4AsO UwxmBw66EAn6oMAq3MD1+8DC67EeWg3EUA2iwE4GccMaXAnb0ArQCwuG8sND0guUVQ/yAA8QUQso vMAr3MQtTK7GsA+edyQmwitsAorSKin/gMPMe6SOcAz14AlH6sX/AMZEJwuLlMC7m8Lz/8u9LnwL 0dALoyAHuiDHxHA4aFuwB4HFAHAIOWwuM2IKgfzFBmySrwCnr5rGS+wE+vAN3IAJnvCfCGG/R0oK flMDALAD3ieyV5zHGuwISVIKoTzIo1w/8We9iazGABAF0uANqnCkGhMUsgwAphCQP/C1uVzB/6DJ nLzH5vLLwUzIDmHM8svAUGAoGQwAdAwU0TzN/1DNYEtt9gC+76AM2zAMv2APNnbOiTA7ngUAkGAo bwsAs7A1swsAuyQUtYAPlIUL2GsMfgsAULAmw8CoQrEPYksw2fQ82+LO1QIO0fAO1vAJ42AKxEAJ R3qF49DMADAHtEAOmXCkelAL5PAIR/+aCblADnbAw+KQsQmhiPnACvEgDPlgpADQC/8XA1+7DPmg C0dqC9wgDMWgCdjQDstQDbSwC+vQDMmAC5fgDMKgD4cKAr6QD75wpJ3QDfkwAwCAA/mglwviDdAQ DtaZDMTQDMVAC7TAaHRtC7aQMslwFrYADMTw13wN1ckADHxdds3CEL7KDa9wCarQCatwCWRwBpvg CaxgB2SwB5/ACppABmRQCZiACXcABoLQCZbACGSABpcACZKgBl0gCH1ZCGQQB5ywCpsA2pOQaJp9 B6tgngKSD+qwDziyDvrAD/4QdKL4gslNEe5AEYq5o2rRDLBQDLPQCrnwCc/wDNAwC8j/EG/nUDb9 AA5D6A0m2A8cQ3StoxDqkAu3UAu5UAuB+Q3ipwvbIY6XGIqRSHf+cJZ/WYLW8pc/VT8SOiAD9g3s MIfxwA/d0A0fSBE9aC0O10juhxJEiA4zKQ/BcLrC4AvIcAzXwAzIkAxf8w0N9A7QVzzpiA8j2g/q 4H49FaHqMHQ5aJJxLCDrgA7hMBP5wKvy0A7vAA959CIhEg/ukHm9lkb8QA88Ld1BIQ3F0AvdkAyt QA2q8Am00AqoIAqqsAv7ceTWEg2Fdw78fQ5X1w/mIKG5QAujcH+/UJfO0AzSYAyvYBTzwG750ED/ sA7TtspDFw7dZw9EpFLvUEz24ILJ/ykg+zBk9uAO+ZAP2VAP/kCg+NDWehndahEO5dAO3qAN4WAO 6bAN6dAN3BAOnGYbRKdvK0h0cfzcBqEPnucP9jB08FY/tOkd7KAO2eAOiSEP6zAO4cDK2/ANyygQ rGYt+uYPr2frRHjr3hiYcugNSe6S9TAOwC1Nbu0QSIbcRmgh7QB33WAMsWANplAKvDALrpAKsjAM +/EOTMgP7UCE3eB+8D50cKx45vAKseAKqKAKv1ALvMAMyeALriA/6UB3P34QCigQ9WBx+3AOxYQj +ZZBApENcMoOlmwh/e2SvDQORPgPBU6m63B38NAh8CAP+uAO8XBr1LZ3h5ft3rEPu//gC+2QDtZQ DsSAC1ZJakzIi0O44PXDDUfWiwhhD9OgLdsA7OugDszgC8wwDS1y3EsDOthXP93nD/AwdNloLQgK bPXzly7CD8XwC+JADL8AfsGQDaly7Lcy63w3hL/C7AkBD8oADLlQirWQDbcw87bwQikClQbB6QcR kSbJabyEDTA+ovsQ9zArd+127RZilqseZPrQ5HJMdfhGkpju5GrBD8MwC6hwDtxgM7uwCsvn7qxO hO1QTPX+6iaKEN5wCqwwC9eAC86wDtGAC6kwC7dwMPlQTPvwl+bQfUp4KxyqavXDoRAqELioodQA DecADdEQLtHgDcZS9dwi6dai/dn/r/U3LhDoAAzW0AzUYCnyQAzOUA3NAAzi0g5MyIAH8Ys2TnTs UEzv4Pj6MKJY95ymDBD/BA4kWNDgQYQJFS5k2NDhQ4gRJU6kWNHiRYP68Cn01w8jQ30H73n8WNIg v4h/cCXs58scQnTm0J0jt21atmfytP0LJopULnLU6nF7Bm2jQH/PXs0r6OzPO4PwmFkr940ivXEx zXWrlo3ZOm/3wIkyVUpcM3viqilTN/BcMngH+02LZzDOrYT7VpFDWK3cOW/LOrUiNmxctX9qRpiY wu7aMlzKcrEbqE9ZPTVr0g0sdmqfwXnJ2NoiGRHdtnPjqLEaheyWOGf8ZIVgcSJZ/zdusZjhsjYw nLlsB9Vpo5THHsG/CqeNQ5hv3jx6++zZi9vxnz158upZz7dPHkF9z/hdALBs4D2O/5KhlNjv+TyN +Nyh/Kwvuzx+Hvnxm/dZ4LhzbEjEoHTyAQMAdBKyjiBnmDMpo2f2CQEAZyA6hr0HHxrHHACwILCe MgbYDKF3aDmHQQczrCzCCStEyJxg0BtoPRU1NMeALz4MccSDslHluIGgSbHG8CSkMCFidMHQHlxK q3GhDXHUUcSE3LEFH3ywyYYeX/h68p8iW0xom2EIwocXJ79EKMocC0oHRCoR4qaVfPQZBphvQHnp yzCPRGgZYAqiUU2F2JySR4PUsf+lnn/8yecfaoZUsU8XD4oGGH8IupDQQm9sk6A3d0zoHVGYGqhB NSlNyJpVClIGQ04NMtRNOBEtCB9t/BMIVT5Z9PMgd7j5B55nsEGnljRjHWhWUGut0hQgBRIyVV8r NQgbvOYhRpljk0Uo0wyZHSjUOA96BxVGBepnGC+fVBUhbGQZyKNXB1JnmmC+K0geagjBA9yPxBWI XFsJYscUegbKh5VyqDXS2oKukVdT9vjhBhUAZpGVnhsegPUigf8huMpaHh1IGkkzfPcgbIIRlL19 zuEFgFgMKqceITj42KKQR0aonFFk3DXlgdrxBuCJVjYImpoHwmcXkvYxRxcAJkb/DmedTerZ2b5e CelUov/BBxlmrKpI6YJ02YWgepAVSGqqrR7o5px3rmhrUUlclKBowq6nmnbCsQhtgq7xBel6/4G7 apuxtpsivMs1SJ6l/rnnG3p2abegeqhh55TEJSJ8IHFucXJTxadmvCC6sy4p8oLtjQaldmgZR5Q9 DarHmnYacCD2hkYXaJveCBp0cbkFav3xiWBPCJ5aNuInrkgR2r2dBRRIMOlqEwInGYHWwWaeXqJW Pfl/ltfa00MTovyooa3nvQEGthe9e4Sywesfc4YxZxbzxa1xdVuflGiVt4OEQxbw+wevdDe/+lFE eP94hjCQgpLEIW+ArgsY+w4o/7mCnEMUCQuS3yBov4hMkBkao9jbzrdB5knEeWs6RbTWtTm2nbAi +DsINPY3I5i9kHWOK+CnxgWneLjDENFIlCeilQ9VNOwg16MfChviDGcI4xvSeFhCotE0geQDTS4U 4BBz5i3IebBZZSiANEQBgAEVBBmt0NU/UIYQe+hwIez4RS0aQQxziEIAVdhGFw/iD1xYcCDyiEUA V3c1IXTAHu3IRrosUo4bgSFNoQoAMpIBgEfYjBtIcyBB/LEPPSpEGvgoAwD28I9XAMAJhRTTIZWx DVexpx+qYyEkO1ANVSiAExTxR1B6sQ10IEALpZuEvjjpjGeA8ormMAcyXjGKdf84YxNFyAQ4ehfB hSDmDQAAxD9cAQAo0PJXDbmQPfrBD9W9Ah3oaMfccKaBcUADAJO4SjoUkTF4JOAJ/zAEAKghEHaA KADNcIY0GfIMc0xDHiIAwC7usQgAhOEc7qBfWxZyjX/AAQCBgCU6ucGPCT0DIs0wBzeI8IZ57AIA l1jHD2hgL3sIAZ8NtYQE6zEJANRiHgiIwj8YYVB5kIMb+WhlUQAQCYXsQx128oo9PECzdxR0C9oY BwAAgA1vdMMa69BGNZjBjXVwIxvTOMY8wgCAOdTjjUKARjwmAIBhMBAh7aiGPXwhDXIsIAfmaAUA EFEPFFRgG86QBTHecYMGXIP/GHD8xjKGARteTIMbzviFOLjBDGo04xauqEYwZsEMcAgCAKLgBgCI oA4+AIAUvmiAFOSxBQD8QhgA+IM7EpIOW3QDF73IhTAmoYhZBEMViQAFL3zBiEbQohShuMQsSuGJ SIiiFqnoRHV9AYpEmEIYsEjEJnQRjEgkwhbSYMg42LUMZ0wDFreYhjJWMQxr0AIW0VhGKYIhjly0 4hrYWEUwlpGLVBTjF6nARTJ0YQpiEOMVuZCGL2CBDGE0lhrIwAUzppGLYGwYF9AABy188Q0OUwMb uDjGTvxhj3toBEhSU5eypigP6Mxjxvd48T/y4Sh65KMf96DHKemBD34QuR/7/6CHPZBm44HJohav iIUsrgGNaWjDGbgQ1jy81I9vkMQcvlVcXAQSD5PZg4T9gAe45JFmEhZkF7QwxStIIYxlQCMaH27r NbSRHWykQx7qqEZ2tKEOeQAnO9yYBqPk4ZHpNEoembrHcfwx6eughx+YPvI/Ni2QTn/6H50WSD2W IY5sKGMZz3hGN6DxjGqIw3Jk9oc6wPWONcMPyQLRx9deDK57+CcfehUIN7hhjmpIwybp0MY1toGN e1BjGu+ARzTK8Q5zNIPa0zDHO8IhjXe8wxrQsMf0ukOP6OQDzUzuTz7g0R0d/6Mf6YqxvIFU737c +2vMiEYyntEMcKAHH+1gx/+9GtYPX+sDXPvQJZn/gWaB2MNUjgKXPir2tYGYoxe7CAYwgmEOHdOk HNEwSj3icR+Upxzl8YiON7aBSXB8g5rcwKQ3yGEOcXiDmt+4hsKBhI+Q5FsgQLe3QIItEFoUAxi4 eEUxhrENWyBDwb2wyj3I3I91sAceJMzHNsAVDlOtQ4r8YAdJ3iEjkxfEHMBwxjJ2AYxkfDYazmCG MaCRj+mdOST6qMvDQ5IPfcGDH/lQjT32QQ5w7CMf1cDHPrQRj32wo5D72OI9+NGO/MCjHv3Ix3z6 wXLOex4eMoKHzL8BDm5MB+HrcMeGHqQrfoDrnQZhdTGacQxrpKMd+jgHOrj/AQ2Fk6QfmVrQ8Bsl fH/4gya9p+ZM/hKTcszz+eYghz664Q1xkCMcNidHN8ZBDuyTQxzfIAc5voGNjYSDyqtQBSqMoQth MMOys+jGP+rhUX6cgz3t0Jc+0AEudUiXeKgnT6sG9uAGAjyH+iuIXgCGXLiFVTgG01qGY1gGXmCG e8CHPUEHRqmHE/mHc2AUehiRc5CR/3u46tieeEhBgYCH/viGaZgHfiiHbOCHfXAGeuAHakgHfhC3 /cgGHLQcb4iHdYg5d1AHb1CHcBCHcgAeTsGHRwkHbrCGN3M3Z7sGNDokYjKlcOjCcDi9LhQHL/TC b+jCsKqjgbCGZ1AGXMAF/14gBvOgB/yjBv9gh77Lh3MAl8drQQKMGZLYBqgYFgI8iGOABVIAh2V4 hW3oBVOIBo3wqGuoC3zwKHVAD3YIjn/YQ35AB48QhwTZhxN8h7rIB2nIFHGQNbITiG+oC32gjH9w B/SoB1z6h24YxIL4BWSAhtA6BlhrFIAxGYMAGIXTQl7LQsthFDaLh3hIh3doh3NoByt6MhWRxoag xsu7BmSAL+wLB8pQN3WBBzEjwLwTiDcLHynqh3cgiXk4inaQIoJYBmYQBl/QhWI4Bm7QhVQoBVxg BcvTF/i4jg+Uh5Cgh4D8jM/ziHo4jhnMlIT0tHFgSE3TlyDzMS/pNHyQov95AMbzUIVVCIVakAVk oIVdqL99kJFfa8F0ETqj8495MLOTtBz/qAczQw7i8QZsAKtwcAZzAIdp2AbDM7N3uw4pKsd5kCLI k7d0HDVG4YeHtD+FDIdMoQf02Aczk4eNwAdZ+4d1tBwHscqD2Id92I5/wI/kg7KB8AdlQAZk0IZv 8AZ2sAdyIIZkAIdq6IijwAf9MBl2kJ6vWYeQ8Ad8yJReaxSTOTnCPLOE6YejwDt508vE1MtoMcuH 4IdVYAVaGAZc0AXYQAVdgAX2iwe+0zsf05dxYBR80BdxQA828wh6WMo2+4d1oIzpyRR1gAp+6Lut 3Ie+I4e4CM1/IAdTCQgAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/arrow_up_grey.gif R0lGODlhBgAEAIAAAP///5mZmSH5BAAAAAAALAAAAAAGAAQAQAIHBBKGm2xvCgA7 ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/icon_mail.gif R0lGODlhEgASALMAAOvr6zMAZv///4KCgsjIyKqqqtHR0ePj4+rq6pycnOHh4Zqamunp6cbGxoCA gM3NzSH5BAAAAAAALAAAAAASABIAQAROEMhJ6wxCFBxKDgNhjaQUnGgaGApCGckgz3NilDjVYdm3 OQ3XpachgkS5pHJJOhF7p8WDodPwBB1sqHLdeD5bnUoVnhwMhLRabTgw37gIADs= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/icon_pdf.gif R0lGODlhEgASALMAAIiIiNnW2+vr67KyvPNwcHBwcOPj4/kEA9uXmcjIyP///+D///m1xeEyMv/g +Mrl4iH5BAAAAAAALAAAAAASABIAQAR3UMhJ6zxLkKa6QscBJFZpCscwLItyBJ9IUmFth2N1H40d GLpBQKDgbGoD4EUheCwCgUcAVEhSDIGEdrv9nTQEr+mAKJcPjDNgSBMS0wQHKEeDLggEBgwkYksw Gw9EEgAHBWs0Dg5QDAwqczMTAQCUlZaIX5maJREAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/nav_bullet2.gif R0lGODlhCgASAIAAAGYAmf///yH5BAEAAAEALAAAAAAKABIAQAIOjI8IkO0Po5y02reulgUAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/nav_prev.gif R0lGODlhEgASAIABAAAAAP///yH5BAEAAAEALAAAAAASABIAQAIXjI+pAb0Po5y0JmAZzrx77lTN ZpHfeRYAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/nav_next.gif R0lGODlhEgASAIABAAAAAP///yH5BAEAAAEALAAAAAASABIAQAIXjI+pAb0Po5y0HmCNy7x7vlUN Jn7miRQAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/nav_toc.gif R0lGODlhEgASAIABAAAAAP///yH5BAEAAAEALAAAAAASABIAQAIVjI+pBrAPo5y02tSyu7z7P2ng SF4FADs= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/npg_logo.gif R0lGODlhjABgAKIAAP///8wSNAsLC+vc37+1t2BgYNhFYON9kiH5BAAAAAAALAAAAACMAGAAQAP/ CLrc/jBKNsgxIWtjzphgKI5kaRJaqq4sa5hwLM/LERyAnX5bviocwCD10r1oyKRSyGlumpjX4GDR pTwPFG7J7cJQrbA4s/Waz+i0ej2pDN4NAuEjFNCF9MpCrhfy2YBpBApwCnMLeoUQh4GNNAQCgw0F Ant3DJCSFJqOnTUBH0NblB+Ug5AFCqQAqwACqQWDlACZqpW0kQqvhrmznr/AwcIOFw61dam4p7kD ArerzZzD0w9WY2IGl9TbChcBGGPg1ytH3MIYONYBgz3q60NkU1TiGebT9C1FYTws2vbbA/CN0yDt n8GDCEvc6BYAEaVbx1DZWrCL1a2EGDMKsxEq/8OHirWOmbJIaNeqVLUGFEh2zFmpXnYsMtJIrGHC inX80SyB4QOGOajcVBzpy1WyVZAu7lTzDREoGkWXCgs4kIhOqY4EVm1xFasZd1vHeU0TMJS3bD48 Cjk7iGpTcGgJlRnLBV1aDfyauvtQDF68FHS92EinIq8UFXIyZNOqIbAXxir0hfH2A4vjx2NwuCX3 gQAUz10vKwET1kVo0Wg8X+twGrXr17AvDzmCoY4siLlwHb3VrIDQWBJjmxDFULfFzsx614kZvFku AsmES4ftTJpzQrEeVDfme7qDKXjuKDqU6c9EQ5IqkI/kBlOeUzNpxR9rw+ltXss0OSOpa/fz3P++ iITbbbJER98737V1SXsg9IHEK9Bt59UbFCYEXSytwcagIQyqdwkjhagkX4beVbMOAEEoY8sd+xW1 0nkylWjCDQfocJUilgixACkkylhNjQXBoN58PiIxxUAGBFlkEmBVFdeSM2xW2go9QtlAk1NuUCWU fmU5xpY+dunlGEpayQBrNqB1pAYepBmKahtUYYE4YE6nBS1ECNEDaRm05VGXhDVlJgR2qWPYXXih eFg7jQ36QKGFAcBopHaRtmY9jjoA6Q6SKoZoPVZgaVOmDFzQFlxHnGVIFDX2EBAUHHhKagNIfrpC jbDyVeagfIYhmQudUjnrIqvZSpCtlg37nRj/NTaLpQcU2qVsBL2O+U2dvFq70LQlwFlVstzKIA+s VGAb7rnopqvuCDiuO0EUbPLy0HLOrLRLUrY4U8mFrQy7bX20nBfRUBeB9Eos2Sn7r02mBJhbcL4o p2K4eBnhSr3VOQcTxnboy5LH5ror8shrbIjIroQQKfIxDDhs4B65tRzzuSzvqNQiMw/qFzg4SOTc Mq/Uex4lqfT2YlIe2wJ00LwdHDTKCQHsw0cf5ycvf0bh8nBuBkvyooq+ROWV1ByxUvXEyhW1Syj7 iXR21hMT3V1gRnRgM8dy1LsSci7pG6EpGqtUb+AP+aav4Hq/LJXUB31t21jwgGuP3P2SbPnlSmbM lmYHD7UdCdHLvVS0xxJyW5sP+K1YEiwF72Yz1FwqZpmA6ZkUE9yOiz0sqqz5zcvTJXGcir4Ho1uj UyGb7S46rSaflMqYw5YAADs= ------=_NextPart_000_0000_01C63092.57902220 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.nature.com/bjc/images/button_go.gif R0lGODlhGQATAKIAAGYzmf///wAAAI1bv1AifQAAAAAAAAAAACH5BAAAAAAALAAAAAAZABMAQANT OLrcvmKACUKYFt+6J4lUKI7hJ5HoaKJZ6oFuvIZWTdXde2o81+sxmWBILBqPxl2QNFsyYU4V1Edt tYC3jVWba2ps3xzAy7m6yFEdYc1uu99rQQIAOw== ------=_NextPart_000_0000_01C63092.57902220 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nature.com/bjc/style.css .searchbar { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #330066; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.searchbar:link { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #330066; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.searchbar:visited { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #330066; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.searchbar:hover { COLOR: #000000 } INPUT { FONT-SIZE: 10px; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } TEXTAREA { FONT-SIZE: 10px; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } SELECT { FONT-SIZE: 10px; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } OPTION { FONT-SIZE: 10px; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } FORM { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; = PADDING-TOP: 0px } .date { FONT-SIZE: 10px; COLOR: #330066; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .issn { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #330066; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .copyright { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #666666; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.copyright:link { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #666666; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.copyright:visited { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #666666; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.copyright:hover { TEXT-DECORATION: underline } .navheader { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #ffffff; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .nav { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.nav:link { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.nav:visited { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.nav:hover { COLOR: #663399 } .navon { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.navon:link { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.navon:visited { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.navon:hover { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } .free { FONT-SIZE: 11px; COLOR: #330066; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .smallnav { FONT-SIZE: 10px; COLOR: #000000; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallnav:link { FONT-SIZE: 10px; COLOR: #000000; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallnav:visited { FONT-SIZE: 10px; COLOR: #000000; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallnav:hover { COLOR: #663399 } .mednav { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.mednav:link { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.mednav:visited { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.mednav:hover { COLOR: #663399 } .bluenav { FONT-SIZE: 11px; COLOR: #663399; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.bluenav:link { FONT-SIZE: 11px; COLOR: #663399; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.bluenav:visited { FONT-SIZE: 11px; COLOR: #663399; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.bluenav:hover { TEXT-DECORATION: underline } .greynav { FONT-SIZE: 11px; COLOR: #666666; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.greynav:link { FONT-SIZE: 11px; COLOR: #666666; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.greynav:visited { FONT-SIZE: 11px; COLOR: #666666; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.greynav:hover { TEXT-DECORATION: underline } .smallbluenav { FONT-SIZE: 10px; COLOR: #663399; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallbluenav:link { FONT-SIZE: 10px; COLOR: #663399; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallbluenav:visited { FONT-SIZE: 10px; COLOR: #663399; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallbluenav:hover { TEXT-DECORATION: underline } .head1 { FONT-WEIGHT: bold; FONT-SIZE: 16px; COLOR: #310063; LINE-HEIGHT: 18px; = FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } H1 { FONT-WEIGHT: bold; FONT-SIZE: 16px; COLOR: #310063; LINE-HEIGHT: 18px; = FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } .toollink { FONT-SIZE: 10px; COLOR: #999999; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.toollink:link { FONT-SIZE: 10px; COLOR: #999999; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.toollink:visited { FONT-SIZE: 10px; COLOR: #999999; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.toollink:hover { COLOR: #310063 } .introtextblue { FONT-SIZE: 11px; COLOR: #330066; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .introtext { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .medtext { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .featured { FONT-SIZE: 13px; COLOR: #310063; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .archivelink { FONT-SIZE: 12px; COLOR: #0000ff; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: underline } .headline { FONT-WEIGHT: bold; FONT-SIZE: 12px; COLOR: #310063; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .text { FONT-SIZE: 10px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .smalltext { FONT-SIZE: 8px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, Helvetica, = sans-serif; TEXT-DECORATION: none } ------=_NextPart_000_0000_01C63092.57902220 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nature.com/bjc/style_article_older.css BODY { FONT-SIZE: small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .body { FONT-SIZE: small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .bodytext { FONT-SIZE: small; COLOR: #000000; LINE-HEIGHT: 133%; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .tablehead { FONT-WEIGHT: bold; FONT-SIZE: small; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .tablecell { FONT-SIZE: small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .tableline { BACKGROUND-COLOR: #000000 } .articletitle { FONT-WEIGHT: bold; FONT-SIZE: 105%; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .smalltext { FONT-SIZE: xx-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smallgrey { FONT-SIZE: xx-small; COLOR: #666666; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smallblue { FONT-SIZE: xx-small; COLOR: #663399; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smalllink { FONT-SIZE: x-small; COLOR: #0000ff; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: underline } A.smalllink:link { FONT-SIZE: x-small; COLOR: #0000ff; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: underline } A.smalllink:hover { COLOR: #663399 } A.smalllink:visited { COLOR: #663399 } .head2 { FONT-WEIGHT: bold; FONT-SIZE: 105%; COLOR: #663399; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } H2 { FONT-WEIGHT: bold; FONT-SIZE: 105%; COLOR: #663399; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .head3 { FONT-WEIGHT: bold; FONT-SIZE: small; COLOR: #663399; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } H3 { FONT-WEIGHT: bold; FONT-SIZE: small; COLOR: #663399; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.head3:hover { TEXT-DECORATION: underline } .head4 { FONT-WEIGHT: bold; FONT-SIZE: small; COLOR: #663399; FONT-STYLE: = italic; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif; = TEXT-DECORATION: none } H4 { FONT-WEIGHT: bold; FONT-SIZE: small; COLOR: #663399; FONT-STYLE: = italic; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif; = TEXT-DECORATION: none } .legend { FONT-SIZE: x-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .tabfn { FONT-SIZE: x-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .reftext { FONT-SIZE: x-small; COLOR: #000000; LINE-HEIGHT: 133%; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } ------=_NextPart_000_0000_01C63092.57902220 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nature.com/bjc/style_article.css BODY { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .body { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .bodytext { FONT-SIZE: x-small; COLOR: #000000; LINE-HEIGHT: 133%; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .tablehead { FONT-WEIGHT: bold; FONT-SIZE: x-small; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .tablecell { FONT-SIZE: x-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .tableline { BACKGROUND-COLOR: #000000 } .articletitle { FONT-WEIGHT: bold; FONT-SIZE: 110%; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .smalltext { FONT-SIZE: 10px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smallgrey { FONT-SIZE: xx-small; COLOR: #666666; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smallblue { FONT-SIZE: xx-small; COLOR: #663399; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smalllink { FONT-SIZE: xx-small; COLOR: #0000ff; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: underline } A.smalllink:link { FONT-SIZE: xx-small; COLOR: #0000ff; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: underline } A.smalllink:hover { COLOR: #310063 } A.smalllink:visited { COLOR: #310063 } .head2 { FONT-WEIGHT: bold; FONT-SIZE: 110%; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } H2 { FONT-WEIGHT: bold; FONT-SIZE: 110%; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .head3 { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #310063; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } H3 { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #310063; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.head3:hover { TEXT-DECORATION: underline } .head4 { FONT-WEIGHT: bold; FONT-SIZE: x-small; COLOR: #310063; FONT-STYLE: = italic; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif; = TEXT-DECORATION: none } H4 { FONT-WEIGHT: bold; FONT-SIZE: x-small; COLOR: #310063; FONT-STYLE: = italic; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif; = TEXT-DECORATION: none } .legend { FONT-SIZE: xx-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .tabfn { FONT-SIZE: xx-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .reftext { FONT-SIZE: x-small; COLOR: #000000; LINE-HEIGHT: 133%; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .linker { FONT-WEIGHT: bold; FONT-SIZE: 110%; COLOR: #0000ff; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } ------=_NextPart_000_0000_01C63092.57902220 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nature.com/bjc/style.css .searchbar { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #330066; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.searchbar:link { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #330066; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.searchbar:visited { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #330066; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.searchbar:hover { COLOR: #000000 } INPUT { FONT-SIZE: 10px; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } TEXTAREA { FONT-SIZE: 10px; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } SELECT { FONT-SIZE: 10px; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } OPTION { FONT-SIZE: 10px; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } FORM { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; = PADDING-TOP: 0px } .date { FONT-SIZE: 10px; COLOR: #330066; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .issn { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #330066; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .copyright { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #666666; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.copyright:link { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #666666; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.copyright:visited { FONT-WEIGHT: bold; FONT-SIZE: 10px; COLOR: #666666; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.copyright:hover { TEXT-DECORATION: underline } .navheader { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #ffffff; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .nav { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.nav:link { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.nav:visited { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.nav:hover { COLOR: #663399 } .navon { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.navon:link { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.navon:visited { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.navon:hover { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } .free { FONT-SIZE: 11px; COLOR: #330066; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .smallnav { FONT-SIZE: 10px; COLOR: #000000; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallnav:link { FONT-SIZE: 10px; COLOR: #000000; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallnav:visited { FONT-SIZE: 10px; COLOR: #000000; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallnav:hover { COLOR: #663399 } .mednav { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.mednav:link { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.mednav:visited { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.mednav:hover { COLOR: #663399 } .bluenav { FONT-SIZE: 11px; COLOR: #663399; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.bluenav:link { FONT-SIZE: 11px; COLOR: #663399; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.bluenav:visited { FONT-SIZE: 11px; COLOR: #663399; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.bluenav:hover { TEXT-DECORATION: underline } .greynav { FONT-SIZE: 11px; COLOR: #666666; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.greynav:link { FONT-SIZE: 11px; COLOR: #666666; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.greynav:visited { FONT-SIZE: 11px; COLOR: #666666; LINE-HEIGHT: 18px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.greynav:hover { TEXT-DECORATION: underline } .smallbluenav { FONT-SIZE: 10px; COLOR: #663399; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallbluenav:link { FONT-SIZE: 10px; COLOR: #663399; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallbluenav:visited { FONT-SIZE: 10px; COLOR: #663399; LINE-HEIGHT: 14px; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.smallbluenav:hover { TEXT-DECORATION: underline } .head1 { FONT-WEIGHT: bold; FONT-SIZE: 16px; COLOR: #310063; LINE-HEIGHT: 18px; = FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } H1 { FONT-WEIGHT: bold; FONT-SIZE: 16px; COLOR: #310063; LINE-HEIGHT: 18px; = FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif } .toollink { FONT-SIZE: 10px; COLOR: #999999; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.toollink:link { FONT-SIZE: 10px; COLOR: #999999; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.toollink:visited { FONT-SIZE: 10px; COLOR: #999999; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } A.toollink:hover { COLOR: #310063 } .introtextblue { FONT-SIZE: 11px; COLOR: #330066; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .introtext { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .medtext { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .featured { FONT-SIZE: 13px; COLOR: #310063; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .archivelink { FONT-SIZE: 12px; COLOR: #0000ff; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: underline } .headline { FONT-WEIGHT: bold; FONT-SIZE: 12px; COLOR: #310063; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .text { FONT-SIZE: 10px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: none } .smalltext { FONT-SIZE: 8px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, Helvetica, = sans-serif; TEXT-DECORATION: none } ------=_NextPart_000_0000_01C63092.57902220 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nature.com/bjc/style_article_older.css BODY { FONT-SIZE: small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .body { FONT-SIZE: small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .bodytext { FONT-SIZE: small; COLOR: #000000; LINE-HEIGHT: 133%; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .tablehead { FONT-WEIGHT: bold; FONT-SIZE: small; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .tablecell { FONT-SIZE: small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .tableline { BACKGROUND-COLOR: #000000 } .articletitle { FONT-WEIGHT: bold; FONT-SIZE: 105%; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .smalltext { FONT-SIZE: xx-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smallgrey { FONT-SIZE: xx-small; COLOR: #666666; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smallblue { FONT-SIZE: xx-small; COLOR: #663399; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smalllink { FONT-SIZE: x-small; COLOR: #0000ff; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: underline } A.smalllink:link { FONT-SIZE: x-small; COLOR: #0000ff; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: underline } A.smalllink:hover { COLOR: #663399 } A.smalllink:visited { COLOR: #663399 } .head2 { FONT-WEIGHT: bold; FONT-SIZE: 105%; COLOR: #663399; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } H2 { FONT-WEIGHT: bold; FONT-SIZE: 105%; COLOR: #663399; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .head3 { FONT-WEIGHT: bold; FONT-SIZE: small; COLOR: #663399; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } H3 { FONT-WEIGHT: bold; FONT-SIZE: small; COLOR: #663399; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.head3:hover { TEXT-DECORATION: underline } .head4 { FONT-WEIGHT: bold; FONT-SIZE: small; COLOR: #663399; FONT-STYLE: = italic; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif; = TEXT-DECORATION: none } H4 { FONT-WEIGHT: bold; FONT-SIZE: small; COLOR: #663399; FONT-STYLE: = italic; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif; = TEXT-DECORATION: none } .legend { FONT-SIZE: x-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .tabfn { FONT-SIZE: x-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .reftext { FONT-SIZE: x-small; COLOR: #000000; LINE-HEIGHT: 133%; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } ------=_NextPart_000_0000_01C63092.57902220 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nature.com/bjc/style_article.css BODY { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .body { FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .bodytext { FONT-SIZE: x-small; COLOR: #000000; LINE-HEIGHT: 133%; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .tablehead { FONT-WEIGHT: bold; FONT-SIZE: x-small; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .tablecell { FONT-SIZE: x-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .tableline { BACKGROUND-COLOR: #000000 } .articletitle { FONT-WEIGHT: bold; FONT-SIZE: 110%; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .smalltext { FONT-SIZE: 10px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smallgrey { FONT-SIZE: xx-small; COLOR: #666666; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smallblue { FONT-SIZE: xx-small; COLOR: #663399; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .smalllink { FONT-SIZE: xx-small; COLOR: #0000ff; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: underline } A.smalllink:link { FONT-SIZE: xx-small; COLOR: #0000ff; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif; TEXT-DECORATION: underline } A.smalllink:hover { COLOR: #310063 } A.smalllink:visited { COLOR: #310063 } .head2 { FONT-WEIGHT: bold; FONT-SIZE: 110%; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } H2 { FONT-WEIGHT: bold; FONT-SIZE: 110%; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .head3 { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #310063; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } H3 { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #310063; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.head3:hover { TEXT-DECORATION: underline } .head4 { FONT-WEIGHT: bold; FONT-SIZE: x-small; COLOR: #310063; FONT-STYLE: = italic; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif; = TEXT-DECORATION: none } H4 { FONT-WEIGHT: bold; FONT-SIZE: x-small; COLOR: #310063; FONT-STYLE: = italic; FONT-FAMILY: Verdana, Arial, Helvetica, sans-serif; = TEXT-DECORATION: none } .legend { FONT-SIZE: xx-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .tabfn { FONT-SIZE: xx-small; COLOR: #000000; FONT-FAMILY: Verdana, Arial, = Helvetica, sans-serif } .reftext { FONT-SIZE: x-small; COLOR: #000000; LINE-HEIGHT: 133%; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } .linker { FONT-WEIGHT: bold; FONT-SIZE: 110%; COLOR: #0000ff; FONT-FAMILY: = Verdana, Arial, Helvetica, sans-serif } ------=_NextPart_000_0000_01C63092.57902220 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nature.com/mailafriend/mailafriend.js function mailafriend(url, form_url, width, height){ if(url=3D=3D0){ url =3D escape(document.URL); } var title =3D escape(document.title).replace(/\+/i, "%2b"); var open_url =3D form_url + "?url=3D" + url + "&title=3D" + title; var params =3D "width=3D" + width + ",height=3D" + height + = ",resizable=3Dyes,location=3Dno,menubar=3Dno,scrollbars=3Dyes,personalbar= =3Dno,status=3Dyes,top=3D10,left=3D10"; window.open(open_url,'mailafriend',params); } ------=_NextPart_000_0000_01C63092.57902220--