TMZ-BioShuttle =E2=80=93 a reformulated = Temozolomide

There is a large = number of=20 effective cytotoxic drugs whose side effect profile, efficacy, and = long-term use in man are well understood and documented over = decades of=20 use in clinical routine e.g. in the treatment of recurrent = glioblastoma=20 multiforme (GBM) and the hormone-refractory prostate cancer = (HRPC). Both=20 cancers are insensitive against most chemotherapeutic = interventions; they=20 have low response rates and poor prognoses. Some cytotoxic agents = can be=20 significantly improved by using modern technology of drug delivery = or=20 formulation. We succeeded to enhance the pharmacologic potency = with=20 simultaneous reduction of unwanted adverse reactions of the highly = efficient chemotherapeutic temozolomide (TMZ) as an example. The = TMZ=20 connection to transporter molecules (TMZ-BioShuttle) resulted in a = much=20 higher pharmacological effect in glioma cell lines while using = reduced=20 doses. This permits the conclusion that a suitable chemistry could = realize=20 the ligation of pharmacologically active, but sensitive and highly = unstable pharmaceutical ingredients without functional = deprivation. The=20 re-formulation of TMZ to TMZ-BioShuttle achieved a nearly 10-fold=20 potential of the established pharmaceutic TMZ far beyond the = treatment of=20 brain tumors cells and results in an attractive reformulated drug = with=20 enhanced therapeutic index.

Keywords: BioShuttle, Carrier Molecules, Drug Delivery, = facilitated=20 Transport, Glioblastoma multiforme (GBM), Reformulation, = Temozolomide=20 (TMZ)

Top

Abstract

Materials=20 and Methods

Results

Discussion

References

Introduction

The medicinal treasures in the pharmacopoeia worldwide, = harboring=20 multi-faced monographs, whose pharmacologic potential albeit their = therapeutic limits are well known. New formulations of = conventional=20 cytotoxic drugs may open a door to a new quality of the = pharmaceutical=20 research. This redesign of =E2=80=9Cold fashioned=E2=80=9D = molecules to highly active=20 pharmaceutical ingredients (API) could be a suitable practice = capable of=20 improve the therapeutic index ¹^-⁴.=20 In case of malignant brain tumors especially in the chemotherapy = of=20 glioblastoma multiforme (GBM) the anti cancer drug temozolomide = (TMZ)=20 (8-carbamoyl-3-methylimidazo = [5,1-d]-1,2,3,5-tetrazin-4(3H)-one)=20 has been well studied ⁵^,=20⁶.=20 It has been shown in recent phase III study, that a simultaneous = therapy=20 with TMZ improves survival rates for patients with GBM treated = with=20 radiotherapy ⁷.=20 Encouraging data ⁸=20 give reason to expand the intervention with TMZ to difficult tumor = types=20 like prostate cancer. Under clinical conditions TMZ was absorbed = rapidly=20 into the blood, and spontaneously decomposed at physiological pH = to the=20 cytotoxic methylating agent = 5-(3-methyltriazeno)-imidazole-4-carboxamide=20 (MTIC). Its half-life and apparent oral systemic clearance values = were 1.8=20 hours and 97 ml/minute/m², however neutropenia and=20 thrombocytopenia limited the tolerable application doses to 1000=20 mg/m². The cytotoxicity of TMZ appears to be elicited = through=20 adduction of methyl groups to O⁶ positions of guanine=20 (O⁶mG) in genomic DNA ⁹=20 followed by recognition of this adduct by the mismatch repair = system=20 (MMR), which can mispair with thymine during the next cycle of DNA = replication ¹⁰^,=20¹¹.

The half-life of TMZ ¹²=20 in plasma and the non-target-gene-specific alkylating mode of = action can=20 lead to undesired adverse reactions, which could result in = discontinuation=20 or interruption of therapy. TMZ therefore seems to be a good = candidate for=20 reformulation, since our new TMZ derivatives could circumvent = these=20 problems by retaining the high efficiency but not the adverse = effects of=20 TMZ.

The coupling of a peptide-based nuclear localization sequence = (NLS)=20 leads to an active nuclear targeting minimizing the above = described=20 handicaps (Drug Design, Development and Therapy, in press). But = due to=20 their higher molecular mass and their physico-chemical = characteristics the=20 transport of TMZ-NLS peptide conjugates alone across the cellular = membrane=20 is poor. Therefore a transport molecule is needed so that a = sufficient=20 concentration of pharmacologically active molecules can reach = their target=20 side inside the nucleus.

Our efforts resulted in suitable ligation modes of TMZ with a = nuclear=20 address peptide which in turn is connected to carrier molecules. = For a=20 better understanding a definition for =E2=80=9Cligation=E2=80=9D = is given in chemistry the=20 meaning of =E2=80=9Cligation reaction=E2=80=9D is the basis of the = Diels-Alder chemistry,=20 which we focus on here.

Such a ligation reaction should meet the following criteria: = (1) rapid=20 course of the reaction, (2) independent from solvent properties, = (3) no=20 side reaction with other functional groups present in the = molecules, (4)=20 without additional coupling-reagents, (5) irreversible chemical = reaction=20 characteristics, and (6) an economical procedure.

Our concept is based on the 'Click Chemistry'. It's = applications are=20 increasingly found in all aspects of drug discovery, ranging from = clue=20 finding through combinatorial chemistry and target-templated = in=20 situ chemistry, to proteomics and DNA research, using = Staudinger and=20 Sharpless conjugation reactions ¹³^-¹⁶.=20 In this regard the 1,3-dipolar cycloaddition developed by Huisgen = has to=20 be considered as a 'cream of the crop' ¹⁷.

Our ligation approach is based on cycloaddition reactions via = the=20 pericyclic Diels Alder Reaction (DAR) with = 'inverse-electron-demand'=20 (DAR_inv), which is a modification of = =CF=80-electron-deficient=20 N-heteroaromatics with electron-rich dienophils ¹⁸.=20 The DAR_inv is, in contrast to DAR, irreversible with = the=20 compounds we used. In this way the pharmaceutic TMZ was coupled to = the=20 modularly structured carrier. We called it TMZ-BioShuttle. During=20 biological tests we reached a dramatically increased efficiency in = two=20 different tumor cell lines in the glioblastoma cell line TP 366 = and in the=20 human prostate cancer cell line DU 145.

The analyses of dilution series indicated for the application = of the=20 TMZ-BioShuttle that the spectra of the treatable tumor types could = be=20 extended.

Materials and Methods

Synthesis of the = TMZ-derivative

A=20 0.2 mol preparation with 42.7 mg=20 = 4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-trien-9-carboxyl= ic=20 acid chloride and 67.4 mg modified tetrazine as well as 28 =C2=B5l = triethylamine were dissolved in chloroform. The reaction process = runs=20 undisturbed and provides a defined product with the molecular = weight (MW)=20 m/e 513.

Synthesis of the = Boc-Lys(TCT)-OH

42=20 mg cyclooctotetraen and 44 mg maleic acid anhydride were resolved = in=20 chloroform and methanol 1 %. The chemical reaction is described by = Reppe=20 ¹⁹.

Solid phase peptide synthesis = of the=20 BioShuttle transporter

For solid phase synthesis of the=20 K(TCT)-NLS-S=E2=88=A9S-transmembrane transport peptide the = Fmoc-strategy was=20 employed in a fully automated multiple synthesizer (Syro II) = ²⁰.=20 The synthesis was carried out on a 0.05mmol = Fmoc-Lys(Boc)-polystyrene=20 resin 1% crosslinked and on a 0.053 mmol Fmoc-Cys(Trt)-polystyrene = resin=20 (1% crosslinked). As coupling agent=20 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium = hexafluorophosphate=20 (HBTU) was used. The last amino acid of the NLS-peptide was = incorporated=20 as Boc-Lys(TCT)-OH. Cleavage and deprotection of the peptide resin = were=20 affected by treatment with 90% trifluoroacetic acid, 5% = ethanedithiol,=20 2.5% thioanisole, 2.5% phenol (v/v/v/v) for 2.5 h at room = temperature. The=20 products were precipitated in ether. The crude material was = purified by=20 preparative HPLC on an Kromasil 300-5C18 reverse phase column (20 = =C3=97 150=20 mm) using an eluent of 0.1% trifluoroacetic acid in water (A) and = 60%=20 acetonitrile in water (B). The peptides were eluted with a = successive=20 linear gradient of 25% B to 60% B in 40 min at a flow rate of 20 = ml/min.=20 The fractions corresponding to the purified protein were = lyophilized.

Coupling of the transmembrane = carrier -=20 and the K(TCT)-NLS-Cys-module

The K(TCT)-NLS-C and the = transport=20 peptide were oxidized in an aqueous solution of 2mg/ml in 20% = DMSO. After=20 five hours the reaction was complete. The oxidation progress was = monitored=20 by analytical C18 reversed-phase HPLC, and then the peptide was = purified=20 as described above. The purified material was characterized with=20 analytical HPLC and laser desorption mass spectrometry in a Bruker = Reflex=20 II.

Reagents and cell = culture

Human=20 glioblastoma (GBM) primary cells (TP 366) ²¹=20 and human prostate cancer cells (DU 145) ²²=20 were provided by the DKFZ division of Biophysics of = Macromolecules. All=20 cell lines were cultured in DMEM (Gibco Cat. No. 12800) = supplemented with=20 10% FCS and maintained in culture at 37=C2=B0C with 5% = CO₂=20 atmosphere and 95% humidity.

Chemotherapy = treatment

Pure=20 temozolomide (TMZ) was purchased from Sigma-Aldrich, Germany (Cat. = No.=20 76899) and the material was subdivided into two parts for = subsequent=20 processing. One part was followed up and coupled to the = transporter=20 molecules. As a control, the second part was dissolved in = acetonitrile 10%=20 (Sigma-Aldrich, Germany) with a final concentration of 0.2% = acetonitrile.

DU 145 and TP 366 cells were seeded (1 =C3=97 10⁵ = cells/ml) in=20 DMEM (control) and in DMEM containing a dilution series of TMZ and = of=20 TMZ-BioShuttle from 50 to 6.25 =C2=B5M respectively. The behavior = of the cells=20 was up to 6 days.

Cell Cycle Analysis

The = effects on=20 the cell cycle distribution were determined by DNA flow cytometry. = Flow=20 cytometric analyses were performed using a PAS II flow cytometer = (Partec,=20 Muenster, Germany) equipped with a mercury vapor lamp (100 W) and = a filter=20 combination for 2,4-diamidino-2-phenylindole (DAPI) stained single = cells.=20 From native probes the cells were isolated with 2.1% citric acid/ = 0.5%=20 Tween 20 according to the method for high resolution DNA and cell = cycle=20 analyses ²³=20 at room temperature. Phosphate buffer (7.2g = Na₂HPO₄₌₂₀=C3=97 2H₂O in 100ml H₂O dest.) pH 8.0 = containing=20 DAPI for staining the cell suspension was performed. Each = histogram=20 represents 30.000 cells for measuring DNA-index and cell cycle. = For=20 histogram analysis, we used the Multicycle program (Phoenix Flow = Systems,=20 San Diego, CA).

Cell viability

For = detection of=20 apoptotic cells and viability, a FACS Calibur flow cytometer = (Becton=20 Dickinson Cytometry Systems, San Jose, CA) was used with filter=20 combinations for propidium iodide. For analyses and calculations, = the=20 Cellquest program (Becton Dickinson Cytometry Systems, San Jose, = CA) was=20 carried out. Each histogram and dot plot represents 10.000 cells. = After=20 preparation according to Nicoletti ²⁴=20 with modifications ²⁵^,=20²⁶,=20 measurements were acquired in the logarithmic mode in Fl-3 and = calculated=20 by setting gates over the first three decades to detect apoptotic = cells.=20 Dead cells are positive for propidium iodide and stained red, = living cells=20 remain unstained. In the logarithmic histogram the positions of = unstained=20 living cells in a are in the first 2 decades the 3^th = decade=20 contains cells with membrane damage, dead cells are placed in the=20 4^th decade.

Top

Abstract

Introduction

Materials=20 and Methods

Discussion

References

Results

Time-Course of Cell Growth and = comet=20 formation in DU 145 prostate cancer and TP 366 glioblastoma cells = provoked=20 by TMZ and TMZ-BioShuttle dilution series

Two different cell = lines=20 originating from different tumor entities like the metastatic = human=20 prostate epithelium adenocarcinoma, herein referred as DU 145 = (Figures 1-2)=20 and TP 366 cells derived from human glioblastoma (Figures 3-4)=20 were used to investigate the pharmacological effect of TMZ and=20 TMZ-BioShuttle.

Figure=20 1

Microscopical=20 monitoring of the human prostate cancer DU 145 cells 2 days = after=20 treatment with TMZ. In the comet column the scale bar = represents 20=20 =C2=B5m. The microscopic pictures were taken in = phase-contrast,=20 enlargement 200=C3=97.=20 (more ...)

Figure=20 2

Microscopical=20 monitoring of the human prostate cancer DU 145 cells 2 days = after=20 treatment with TMZ-BioShuttle. In the comet column, the = scale bars=20 in the maps represent 20 =C2=B5m. The microscopic pictures = were taken in=20 phase-contrast,=20 (more ...)

Figure=20 3

Microscopic and=20 comet assay studies of untreated TP 366 cells and treated = with=20 various concentrations of TMZ; the scale bar represents=20 = 20=C2=B5m.

Figure=20 4

Microscopic and=20 comet assay of untreated TP 366 glioblastoma cells, and 6 = days after=20 treatment with TMZ-BioShuttle; the scale bar represents = 20=C2=B5m.=20 Microscopic magnification is 200-fold in the phase contrast=20 = microscope.

To learn more about the DNA damage and cell death in the two = different=20 cell lines after treatment with TMZ as well as with TMZ-BioShuttle = using=20 the identical dilution series, we carried out comet assays in = parallel=20 probes (right columns of the figure 1=20 and 2).=20 Basically the untreated cultures of DU 145 prostate cancer cells = and TP=20 366 cells did not exhibit fragmented DNA.

DU 145 Prostate cancer = cells

In=20 order to determine the sensitivity of these cells we used a = dilution=20 series in a range from 50 to 6.25 =C2=B5M of TMZ and = TMZ-BioShuttle=20 respectively.

Two days after treatment with the TMZ final concentrations = 6.25, 12.5=20 and 25 =C2=B5M, the DU 145 cells seemed to be unfazed and no = visual change in=20 the phenotype could be observed under the light microscope. = Counting the=20 corresponding cell numbers offered a hardly detectable decrease of = the=20 cell number (from 1.15 to 1.05 =C3=97 10⁶ cells) if = anything=20 compared to the untreated control with 1.12 =C3=97 10⁶ = cells. Only=20 the probe treated with 25 =C2=B5M TMZ revealed a decrease to 0.844 = =C3=97=20 10⁶ cells (Figure 1).=20 The comet assay study indicated a higher sensitivity and exhibits=20 fragmented DNA in the probes which were treated with 12.5, 25 and = 50 =C2=B5M=20 TMZ. The samples treated with 50 =C2=B5M TMZ displayed a decrease = of the cell=20 number to 0.628 =C3=97 10⁶. Additionally in the cell = culture medium=20 an increasing number of dead, clumped DU 145 cells could be = observed.

TP 366 glioblastoma = cells

Light=20 microscopical studies showed a reduced cell population after = treatment=20 with 6.25 =C2=B5M TMZ for 6 days which was increased further = diminished under=20 two fold application doses (12.5; 25 =C2=B5M) from 6.2 =C3=97 = 10⁵cells=20 (untreated control) to 5.3; 4.8, and 2.1 =C3=97 10^{5 =}cells. In the TP=20 366 cells the TMZ probe treated with 50 =C2=B5M, however, the cell = population=20 remained at the level of the 25 =C2=B5M treated cells (2.1 =C3=97 = 10⁵⁼²⁰cells) and may reach a saturation level.

After 6 days treatment with 6.25 =C2=B5M TMZ (figure 1=20 and 2)=20 the TP 366 cells showed differently sized and fragmented dead = cells,=20 sporadic comet structures and shrunken nuclei. In relation to the=20 increased application doses an increase of fractionated DNA and = shrunk=20 nuclei could be observed. The TP 366 probe treated with 50 =C2=B5M = TMZ=20 exhibited sporadic comets and almost condensed nuclei. The probes = treated=20 with TMZ-BioShuttle displayed a deviant behavior. The 6.25 =C2=B5M = TMZ-BioShuttle treated cells offer no DNA fragmentation, but their = nuclei=20 seemed to be partly swollen and diminished (figure 2).=20 The latter fraction was increasing in accordance to the increased=20 application doses. In addition the total cell count of the TMZ = treated=20 samples was lower, compared to the cell number in the control and = cells=20 treated with TMZ-BioShuttle.

The comet assay study detected no DNA fragmentation in the = untreated=20 control TP 366 cells until 144 hours. After application of = TMZ-BioShuttle=20 (6.25 =C2=B5M) and more, much more DNA-fragments could be observed = (figure 4).=20 Indeed the use of higher application doses enhanced DNA = fragmentations and=20 the ratios of shrunk nuclei of TP 366 (figure 4=20 right column).

Cell Cycle Studies

Here we = present=20 measurements of the cell activities like the cell cycle analysis = using the=20 flow cytometric method and a calculation of the percentage of = cells in=20 different phases of the cell cycle. These data were obtained after = treatment with TMZ and the TMZ-BioShuttle in depency on the = application=20 dose. We determined the cell cycle behaviour of TP 366 glioma = cells and DU=20 145 prostate cancer cells. To investigate the influence of TMZ = with and=20 without BioShuttle transporter we performed a dose-response = analysis of=20 the cell cycle shown in Figures 5=20 and 6.

Figure=20 5

The cell = cycle=20 distribution in TP 366 glioblastoma cells dependent on the = applied=20 concentration of TMZ (right column) and TMZ-BioShuttle (left = column)=20 6 days after treatment. The axes of coordinates represent = the cell=20 number; the abscissae=20 (more ...)

Figure=20 6

The cell = cycle=20 ratio of DU 145 prostate cancer cells dependent on the = applied=20 concentration of TMZ (right column) and TMZ-BioShuttle (left = column)=20 2 days after treatment. The axes of coordinates represent = the cell=20 number; the abscissae represent=20 (more ...)

TP 366 glioblastoma cells = treated by TMZ=20 and TMZ-BioShuttle dilution series

Figure 5=20 exhibits the cell cycle distribution of TP 366 cells 6 days after=20 treatment with increasing concentrations of TMZ and TMZ-BioShuttle = is=20 shown in figure 5.=20 The cell cycle distribution is signed as G1 phase, S phase and the = G2/M=20 phase. These cells show a diploid cycle (red coloured). The plot = of the=20 untreated control is demonstrated (figure 2,=20 line 1) and exhibits a G1 cell fraction of 86.4 % and a G2 cell = fraction=20 5.7 %. Looking the TMZ treated cells the contingent of cells in = the S=20 phase amounts to 7.8 %. In comparison to the S phase fraction of = untreated=20 control the percentage of S phase cells treated with 6.25 =C2=B5M = TMZ is=20 increased to 11.1 %. The doubling of the TMZ dose to 12.5 =C2=B5M = results in a=20 slightly decrease of the S phase fraction to 9.4 %. The further = increase=20 of the TMZ concentration to 25 =C2=B5M and 50 =C2=B5M has barely = influenced the=20 amount of the cells in the S phase with 9.1 % and 9.8 % = respectively.=20 Regarding the G2 phase we observed a dose dependent linear = increase of the=20 cell ratio. A concentration of 6.25 =C2=B5M depicted an increase = of cells from=20 5.7 % (control) to 10.2 %. The TMZ dose of 12.5 =C2=B5M results in = a scarcely=20 increase to 10.7 %, but the doubling of the TMZ concentration to = 25 =C2=B5M and=20 further to 50 =C2=B5M resulted in an intense increase of the cell = fraction in=20 the G2/M phase with 15.9 % and 21.3 % respectively. The analysis = of the=20 dose dependent effect on the G1 phase exhibited the following = trend: the=20 starting dose rate was 6.25 =C2=B5M TMZ, doubling of the doses to = 25 and to 50=20 =C2=B5M showed a reciprocal proportionality to the percentage of = G1 cells,=20 74.8% and 68.8% (figure 2,=20 right column).

The TMZ-BioShuttle treated TP 366 cells presented a cell cycle=20 behaviour strongly differing from the untreated control and from = the TMZ=20 treated cells.

The probe treated with 6.25 =C2=B5M evidenced a reduced cell = fraction in G1=20 phase of 70.6% already. The TP366 cells treated with doses 12.5 = and 25 =C2=B5M=20 indicate G1 ratios of 57.9 and 37.6% respectively. Especially the = data of=20 the G2/M phase are demonstrative. From 6.25 =C2=B5M up to 25 = =C2=B5M we observed an=20 increase of the ratio of cells in G2/M from 19.1 %, via 28.6 % to = 37.6 %.=20 In comparison with the corresponding TMZ data, we found a = continuous G2/M=20 enhancement with the factor 2 starting at 6.25 =C2=B5M! to 25 = =C2=B5M and a factor 3=20 in the probes treated with 12.5 =C2=B5M.

Due to the high amount of dead cells the estimation of the cell = cycle=20 distribution in TP 366 cells treated with 50 =C2=B5M = TMZ-BioShuttle was=20 difficult to perform and to analyse. It shows an increase of the = cell=20 fraction in the G1 phase to 68.8% which is identical to the = corresponding=20 probe treated with TMZ. Consistently increased amounts of the S = phase=20 cells could be detected compared to both the S phase in the = control and=20 the corresponding probes treated with TMZ. The trend of G2/M phase = cells=20 turned to the opposite direction. In the S phase not definitive = trend=20 arose from the applied dose.

Cell cycle behaviour of DU 145 = cells=20 after treatment with TMZ and TMZ-BioShuttle dilution = series

At a=20 first glance the histograms reveal a lower sensitivity of DU 145 = prostate=20 cells against TMZ treatment compared to the results of TP 366 = cells. The=20 untreated DU 145 control exhibits a cell cycle distribution as = follows: G1=20 =E2=80=93 58.5%; S phase =E2=80=93 29.8% and G2/M phase 11.6%. The = ratio of TMZ treated=20 cells in the G2/M phase amounts to 12.8%; 15.4% and 23.5% and is=20 constantly increasing in correlation to the application doses of = 6.25;=20 12.5 and 25 =C2=B5M.

The percentage of the S phase cells after treatment with the = above=20 described concentrations were almost constant 29.5% and close to = the=20 control. The cells in the G1 fractions treated with increasing=20 concentrations up to 25 =C2=B5M of TMZ presented a moderate but = uniform,=20 continuous decrease from 58.5% (control), via 57.5%, 56.4%, to = 48.6 % and=20 then a strong decline to 29.8%. The DU 145 probe treated with 50 = =C2=B5M TMZ=20 showed 22.3% G2/M phase cells and a dramatic increase of the S = phase cell=20 fraction to 47.7%.

The DU 145 cells treated with the TMZ-BioShuttle under = identical=20 conditions offered a cell cycle behaviour which strongly differs = from the=20 TMZ probes. The percentage of cell fractions in G1 phase seemed to = be=20 nearly constant 58.5% comparing the untreated control versus the = treated=20 cells with concentrations 6.25=C2=B5M 59.2 %and 12.5 =C2=B5M = 57.4%. The=20 concentrations of 25 and 50 =C2=B5M gave rise to a marked decrease = of the=20 percentage of cells from 45.5% to 20.7% in G1 which corresponds to = one-third of the related TMZ treated probe!

The relative amounts of S phase cells in the concentration = series with=20 increasing TMZ-BioShuttle doses of 6.25, 12.5, 25, and 50 =C2=B5M = offered a=20 reciprocal proportionality and showed a small but continuous = decrease of=20 cell number from 29.8% (control), via 28.8%, 28.1%, 27.1%, to = 24.2%=20 respectively. It is important to note that the latter result = showed a=20 strong reduction comparing 47.7% (TMZ) to 24.2% (TMZ-BioShuttle) = which=20 equates a degression of 50%. The concentration series with = increasing=20 amounts of TMZ-BioShuttle indicated a direct concentration = dependence and=20 displayed a moderate increase of the cell number of DU 145 cells = in the=20 G2/M fraction from 11.6% (control) to 11.9% in the 6.25 =C2=B5M = probe via 12.5,=20 25 to 50 =C2=B5M. A strong rise of the S phase cells from 14.6% = via 27.4% to=20 55.1% was shown. Doubling the applied dose increased cell number = in the=20 G2/M phase mote than 100%! Additionally, the direct comparison of = the=20 probe treated with 50 =C2=B5M TMZ-BioShuttle with the = corresponding TMZ probe=20 of DU 145 cells showed a dramatic increase in the percentage of = cells in=20 the G2/M phase (from 22.3% to 55.1%), revealing a G2/M block.

Top

Abstract

Introduction

Materials=20 and Methods

Results

References

Discussion

The number of old-fashioned cytotoxic drugs, whose = effectiveness is=20 well understood, is multi-faced. However, if highly effective = substances=20 do not reach their target site after application, what is their = benefit?=20 Therefore questions about the bioavailability remain to be = answered,=20 whereby the concentration in the bloodstream is not meant here, = but rather=20 the concentration directly at the site of pharmacological action, = like the=20 genomic DNA in tumor cell nuclei.

A substantial progress in the drug development will be achieved = by=20 improvement of the delivery and subcellular targeting of the drug = as yet=20 unappreciated and meaningless.

The BioShuttle delivery and targeting platform, facilitating = the=20 transport of DNA derivatives into living cells was described = ²⁷^,=20²⁸=20 as well as transport of diagnostics into the cytoplasm and nuclei = of tumor=20 tissues ²⁹^,=20³⁰.=20 There is no doubt that constructs like the TMZ-BioShuttle, as an = example,=20 could play a helpful role in the treatment of cancer. The design = of such=20 shuttles needs to incorporate features that reduce undesired = adverse=20 reactions but maintains the efficacy.

We selected the highly efficient chemotherapeutic TMZ as a = qualified=20 candidate, since encouraging results in treatment of in brain = tumors=20 ³¹=20 remain unendorsed in the treatment of hormone-refractory prostate = cancer=20 (HRPC) ³².

Parallel sets of experiments with TP 366 glioma cells and DU = 145=20 prostate cancer cells were carried out and confirmed a lesser = sensitivity=20 of DU 145 prostate cancer cells against TMZ treatment. Whereas the = TP 366=20 cells showed an increased DNA damage after TMZ treatment up to a = final=20 concentration of 6.25 =C2=B5M, the DU 145 cells exhibited very few = DNA damage=20 measured by comet assay. The increase of the application dose = however did=20 not induce an increased number of comets (figure 1).=20 This phenomenon was already documented in studies with = ceramide-induced=20 cell death ³³.

In DU 145 cells we compared the dose-dependent application of = TMZ and=20 TMZ-BioShuttle of seeded versus harvested cells after 48 hours. In = comparison to the control (1.12) a linear inverse proportionality = (1.15;=20 1.05; 0.844; and 0.628) to the dilution series of 6.25; 12.5; 25; = and 50=20 =C2=B5M TMZ was demonstrated.

These data permit to assume a minimum of TMZ application dose = between=20 25 and 12.5 =C2=B5M. Dilution series with 50 =C2=B5M to 6.25 = =C2=B5M of TMZ-BioShuttle=20 showed an increase of shrunk nuclei (figures 2=20 and 4).=20 The TMZ-BioShuttle revealed the identical subthreshold in DU 145 = cells but=20 the quotient 0.414 at 50 =C2=B5M suggests a higher pharmacological = potential.

The results achieved with both cell lines (TP 366 and DU 145) = treated=20 with the TMZ-BioShuttle differ in the expected augmentation of DNA = comets:=20 All cells were visibly swollen, but we could not detect an = increased=20 number of comets. This suggests a decondensation of chromatin in = the=20 nuclei. This happens when chromosomes are exposed to DNA = replication=20 inhibition caused by failure to constitute compact chromatin areas = during=20 mitosis ³⁴.=20 It could be explained with the involvement of the transcription of = genes=20 expressing histone regulating proteins responsible for formation = of the=20 chromatin structure and for the compact package of DNA ³⁵.

We investigated the cell cycle of TP366 after treatment of the=20 glioblastoma cells with TMZ. It interfered with the cell cycle and = exhibited a decreased number of cells in the S phase fraction as = shown 144=20 hours after TMZ-application when a contingent of the S phase cells = of 8%=20 was detectable.

The phenomenon of a reduced S phase (8% versus control 11%) in = the TMZ=20 treated TP 366 cells is not contradictory to the common effects of = alkylating agents which cause a retardation of the rate of cell = division=20 ³⁶.=20 A possible explanation for the strongly decreased S phase cell = number in=20 the TMZ-BioShuttle treated probes would be the existence of a S = phase cell=20 cycle arrest as documented in a bimodal TMZ/ interferon-=CE=B2 = (IFN-=CE=B2) study=20 ³⁷.=20 Our flow cytometry experiments also displayed a strong cell cycle = arrest=20 in the S phase ³⁸.=20 An interesting criterion for a prolonged late S/G2 phase suggests = the=20 implication of the histone acetyltransferase 1 (HAT1) which = participates=20 in recovering block-mediated DNA damages ³⁹.

The fact that the glioblastoma cells arrest in the G2/M phase = after=20 TMZ-treatment was documented by Hirose et al. ⁴⁰=20 and could be confirmed with the TP 366 cells. Moreover the = treatment with=20 TMZ-BioShuttle resulted in a clearly increased G2/M phase of 72%. = It seems=20 to be attributed to interactions of TMZ and TMZ-BioShuttle with = the=20 mitogen-activated protein (MAP) kinase p38=CE=B1, which is = activated by the=20 mismatch repair system (MMR) and is responsible for the = TMZ-induced G2/M=20 block ⁴⁰.

After cell exposure to the TMZ-BioShuttle for 144 hours, the = observed=20 strong increase of the G2 phase cells of TP 366 cells possibly = originate=20 from the already documented inhibition of the RNA and protein = syntheses,=20 which are necessary for the successful completion of G2 and the = initiation=20 of mitosis. These G2-arrested cells were found to be deficient in = certain=20 proteins that may be specific for the G2-mitotic transition = ⁴¹.=20 The obstruction of the cell cycle process is caused by the stop of = this=20 transition and results in the decrease of the G1 phase cell = fraction (26%)=20 of the TMZ-BioShuttle treated TP 366 cells which appear to be = consequence=20 of their disability passing in the mitotic process.

A sensitivity of DU 145 and TP 366 cells against TMZ and a = dramatically=20 increased sensibility against TMZ-BioShuttle is shown in figure 4.=20 The present data document a different cellular contumaciousness to = TMZ=20 treatment. A real effectiveness of the pure TMZ in DU 145 cells = could not=20 be observed, whereas in contrast clear cell killing effects, = caused by=20 TMZ-BioShuttle, were detected.

It is important to note that the TMZ-BioShuttle treatment of DU = 145 and=20 the TP 366 cells redounds to cell killing effects as shown in = figure 4.

As a general rule the different sensitivity of tumor cells = against=20 chemotherapeutics is dependent on multiple mechanisms like = multiple drug=20 resistance systems. The relative low sensitivity of DU 145 = prostate cancer=20 cells after treatment with TMZ is evident, and the disappointing = results=20 of TMZ trials of prostate cancer can be explained by the increased = O⁶-methylguanine-DNA methyltransferase (MGMT) repair = activity.=20 DU 145 cells show an increased MGMT activity ⁴²,=20 associated with the decrease of the pharmacologic effect after = alkylating=20 with TMZ alone. The increased MGMT expression and activity = correlates with=20 the malignant phenotype ⁴³.=20 We regard the potential utility of this epigenetic alteration as = an=20 appropriate biomarker for prostate cancer ⁴⁴=20 and an important prognostic feature for the clinical outcome in=20 glioblastoma ⁴⁵.=20 The fact that die blood brain barrier (BBB) no presents an hurdle = for TMZ=20 could explain the higher pharmacological effects of TMZ in glioma = cells.=20 It is important in so far that the delivery and the targeting of = active=20 substances play a decisive role and must be further scrutinized. = The=20 TMZ-BioShuttle could be an appropriate candidate.

The physico-chemical properties of TMZ which have an impact on = its=20 bioavailability limit its pharmacological effectiveness. Despite = the=20 benefit of the concomitant treatment with radiotherapy plus TMZ,=20 hematologic toxic effects in patients treated with TMZ are = documented in=20 multicenter studies by Stupp ⁴⁶.=20 A TMZ-derivatization with targeting transporters molecules and = subcellular=20 address components holds tremendous potential to optimize = treatment of=20 diseases. Enhanced cellular delivery and active transport of TMZ = into the=20 cell nuclei as site of pharmacological action permit to expect = lower=20 application doses with concomitantly decreased limiting = side-effects.

Our shuttle, designed for facilitating the rapid transport = across=20 cellular membranes, improved their own delivery and their own = targeting=20 under perpetuation of the pharmacological activity in cells and = tissues=20 while protecting cells in the bloodstream by omission of undesired = side-effects like:

Strong suppression of the peripheral lymphocytes result in=20 discontinuation of therapy and problems associated with systemic = drug=20 administrations, which are:

even biodistribution of pharmaceuticals throughout the = body;
the lack of drug specific affinity toward a = pathological=20 site;
the necessity of a large total dose of a drug to = achieve high=20 local concentration;
non-specific toxicity and strong adverse side-effects = due to=20 high drug doses ⁴⁷^,=20⁴⁸.

The application of the TMZ-BioShuttle could minimize the = handicap of=20 TMZ on the therapy of patients with brain tumors but the = establishment of=20 the TMZ-BioShuttle necessitates new ways for the synthesis. = Conditions=20 which hampered the above postulated criteria like rapid and whole=20 concurrent chemical reactions in aqueous solution at room = temperature for=20 a proper chemical ligation of functional peptides could be = circumvented=20 using the 'inverse-electron-demand' of the Diels Alder = Reaction.

Thus, TMZ-BioShuttle has been reformulated to decrease the = toxic=20 features in normal cells but retain the pharmacologic behavior in = target=20 cells; this was achieved as follows: coupling the amide group of = the TMZ=20 with a tetrazine which acts as dien-component and connects the NLS = module=20 with the tridecadien (TCT) component operating as dienophil.

The presented publication shows that a proper chemistry = contributes to=20 the optimization of the pharmacological properties of the already=20 efficient pharmaceutics like TMZ.

The novel properties of the TMZ-BioShuttle could give reason to = the=20 extension to tumor types like prostate cancer, especially in = hormone=20 refractory situations.

=E2=80=8B=20

Figure=20 7

The dose = dependent=20 effects of TMZ (C/D) as well as TMZ-BioShuttle (A/B) in the = cell=20 cycle behaviour of TP366 glioma (A/C) and DU 145 prostate = cancer=20 (B/D) cells. =E2=99=A6 G1phase; =E2=96=A0 S phase; =E2=96=B2 = G2/M=20 phase

Acknowledgments

The work in this article was done in close collaboration with = Peter=20 Lorenz and Heinz Fleischhacker of our group. We cordially thank = Dr.=20 Christian Kliem and Dr. Jochen vom Brocke for critically reading = the=20 manuscript and stimulating discussions.

Abbreviations

DAR: Diels-Alder-Reaction, GBM: Glioblastoma Multiforme, HAT1: = Histone=20 Acetyltransferase 1, IFN-=CE=B2: Interferon-=CE=B2, MGMT:=20 Methylguanine-DNA-Methyltransferase, NLS: Nuclear Localization = Sequence,=20 TCT:=20 = Tetracyclo-[5.4.2^1,7.O^2,6.O^8,11]3,5-diox= o-4-aza-9,12-tridecadien,=20 TMZ: Temozolomide.

Top

Abstract

Introduction

Materials=20 and Methods

Results

Discussion

References

Lambert T, Recht M, Valentino LA. et al. = Reformulated=20 BeneFix: efficacy and safety in previously treated patients with=20 moderately severe to severe haemophilia B. Haemophilia. 2007;13:233=E2=80=9343. [PubMed]

Johnson JL, Yalkowsky SH. Reformulation of a = new=20 vancomycin analog: an example of the importance of buffer species = and=20 strength. AAPS PharmSciTech.=20 2006;7:E5. [PubMed]

O'Riordan TG. Optimizing delivery of inhaled=20 corticosteroids: matching drugs with devices. J Aerosol Med. 2002;15:245=E2=80=9350. [PubMed]

Roy V, Perez EA. New therapies in the = treatment of=20 breast cancer. Semin Oncol.=20 2006;33:S3=E2=80=93S8. = [PubMed]

Marchesi F, Turriziani M, Tortorelli G. et = al. Triazene=20 compounds: mechanism of action and related DNA repair systems. = Pharmacol Res. 2007;56:275=E2=80=9387. [PubMed]

Danson SJ, Middleton MR. Temozolomide: a = novel oral=20 alkylating agent. Expert Rev = Anticancer=20 Ther. 2001;1:13=E2=80=939. [PubMed]

Shinoura N, Yamada R, Tabei Y. et al.=20 [Temozolomide-temodal.]. Gan To = Kagaku=20 Ryoho. 2008;35:543=E2=80=937. [PubMed]

Mutter N, Stupp R. Temozolomide: a milestone = in=20 neuro-oncology and beyond? Expert = Rev=20 Anticancer Ther. 2006;6:1187=E2=80=93204.=20 [PubMed]

Denny BJ, Wheelhouse RT, Stevens MF. et al. = NMR and=20 molecular modeling investigation of the mechanism of activation of = the=20 antitumor drug temozolomide and its interaction with DNA. = Biochemistry. 1994;33:9045=E2=80=9351. [PubMed]

10.

Cai Y, Wu MH, Xu-Welliver M. et al. Effect of = O6-benzylguanine on alkylating agent-induced toxicity and = mutagenicity. In=20 Chinese hamster ovary cells expressing wild-type and mutant=20 O6-alkylguanine-DNA alkyltransferases. Cancer Res. 2000;60:5464=E2=80=939. [PubMed]

11.

Hirose Y, Kreklau EL, Erickson LC. et al. = Delayed=20 repletion of O6-methylguanine-DNA methyltransferase resulting in = failure=20 to protect the human glioblastoma cell line SF767 from=20 temozolomide-induced cytotoxicity. J=20 Neurosurg. 2003;98:591=E2=80=938. [PubMed]

12.

Riccardi A, Mazzarella G, Cefalo G. et al.=20 Pharmacokinetics of temozolomide given three times a day in = pediatric and=20 adult patients. Cancer Chemother = Pharmacol.=20 2003;52:459=E2=80=9364. = [PubMed]

13.

Kolb HC, Sharpless KB. The growing impact of = click=20 chemistry on drug discovery. Drug = Discov=20 Today. 2003;8:1128=E2=80=9337. [PubMed]

14.

Kolb HC, Finn MG, Sharpless KB. Click = Chemistry:=20 Diverse Chemical Function from a Few Good Reactions. Angew Chem Int Ed Engl. 2001;40:2004=E2=80=9321. [PubMed]

15.

Kohn M, Breinbauer R. The Staudinger = ligation-a gift to=20 chemical biology. Angew Chem Int = Ed Engl.=20 2004;43:3106=E2=80=9316. [PubMed]

16.

Chandra RA, Douglas ES, Mathies RA. et al. = Programmable=20 cell adhesion encoded by DNA hybridization. Angew Chem Int Ed Engl. 2006;45:896=E2=80=93901. [PubMed]

17.

Rostovtsev VV, Green LG, Fokin VV. et al. A = stepwise=20 huisgen cycloaddition process: copper(I)-catalyzed regioselective=20 "ligation" of azides and terminal alkynes. Angew Chem Int Ed Engl. 2002;41:2596=E2=80=939. [PubMed]

18.

Bachmann WE, Deno NC. The Diels-Alder = Reaction of=20 1-Vinylnaphthalene with a,@- and a,p,y,G- Unsaturated Acids and=20 Derivatives. J Americ Chem Soc.=20 1949;71:362=E2=80=933.

19.

Reppe W, Schlichting O, Klager K. et al. = Cyclisierende=20 Polymerisation von Acetylen I. Justus=20 Liebigs Annalen der Chemie. 1948;560:1=E2=80=9392.

20.

Merriefield RB. Solid Phase Peptide = Synthesis. I The=20 Synthesis of a Tetrapeptide. J = Americ Chem=20 Soc. 1963;85:2149=E2=80=9354.

21.

Ahn JY, Hu Y, Kroll TG. et al. PIKE-A is = amplified in=20 human cancers and prevents apoptosis by up-regulating Akt. = Proc Natl Acad Sci U S A. 2004;101:6993=E2=80=938. [PubMed]

22.

Stone KR, Mickey DD, Wunderli H. et al. = Isolation of a=20 human prostate carcinoma cell line (DU 145). Int J Cancer. 1978;21:274=E2=80=9381. [PubMed]

23.

Ehemann V, Sykora J, Vera-Delgado J. et al. = Flow=20 cytometric detection of spontaneous apoptosis in human breast = cancer using=20 the TUNEL-technique. Cancer Lett.=20 2003;194:125=E2=80=9331. [PubMed]

24.

Nicoletti I, Migliorati G, Pagliacci MC. et = al. A rapid=20 and simple method for measuring thymocyte apoptosis by propidium = iodide=20 staining and flow cytometry. J = Immunol=20 Methods. 1991;139:271=E2=80=939. [PubMed]

25.

Singer S, Ehemann V, Brauckhoff A. et al.=20 Protumorigenic overexpression of stathmin/Op18 by gain-of-function = mutation in p53 in human hepatocarcinogenesis. Hepatology. 2007;46(3):759=E2=80=9368. [PubMed]

26.

Tschaharganeh D, Ehemann V, Nussbaum T. et = al.=20 Non-specific Effects of siRNAs on Tumor Cells with Implications on = Therapeutic Applicability Using RNA Interference. Pathol Oncol Res. 2007;13:84=E2=80=9390. [PubMed]

27.

Braun K, Peschke P, Pipkorn R. et al. A = biological=20 transporter for the delivery of peptide nucleic acids (PNAs) to = the=20 nuclear compartment of living cells. J Mol=20 Biol. 2002;318:237=E2=80=9343. [PubMed]

28.

Braun K, von BL, Pipkorn R. et al. = BioShuttle-mediated=20 plasmid transfer. Int J Med Sci.=20 2007;4:267=E2=80=9377. = [PubMed]

29.

Heckl S, Debus J, Jenne J. et al. CNN-Gd(3+) = Enables=20 Cell Nucleus Molecular Imaging of Prostate Cancer Cells: The Last = 600 nm.=20 Cancer Res. 2002;62:7018=E2=80=9324. [PubMed]

30.

Heckl S, Pipkorn R, Waldeck W. et al. = Intracellular=20 Visualization of Prostate Cancer Using Magnetic Resonance Imaging. = Cancer Res. 2003;63:4766=E2=80=9372. [PubMed]

31.

Newlands ES, Blackledge GR, Slack JA. et al. = Phase I=20 trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). = Br J Cancer. 1992;65:287=E2=80=9391. [PubMed]

32.

van Brussel JP, Busstra MB, Lang MS. et al. A = phase II=20 study of temozolomide in hormone-refractory prostate cancer. = Cancer Chemother Pharmacol. 2000;45:509=E2=80=9312. [PubMed]

33.

Monti B, Zanghellini P, Contestabile A.=20 Characterization of ceramide-induced apoptotic death in cerebellar = granule=20 cells in culture. Neurochem Int.=20 2001;39:11=E2=80=938. = [PubMed]

34.

Lukusa T, Fryns JP. Human chromosome = fragility.=20 Biochim Biophys Acta. = 2008;1779:3=E2=80=9316. [PubMed]

35.

Kristeleit R, Stimson L, Workman P. et al. = Histone=20 modification enzymes: novel targets for cancer drugs. Expert Opin Emerg Drugs. 2004;9:135=E2=80=9354. [PubMed]

36.

Bignold LP. Alkylating agents and DNA = polymerases.=20 Anticancer Res. 2006;26:1327=E2=80=9336. [PubMed]

37.

Park JA, Joe YA, Kim TG. et al. Potentiation = of=20 antiglioma effect with combined temozolomide and interferon-beta.=20 Oncol Rep. 2006;16:1253=E2=80=9360. [PubMed]

38.

Thomas HC, Lame MW, Wilson DW. et al. Cell = cycle=20 alterations associated with covalent binding of monocrotaline = pyrrole to=20 pulmonary artery endothelial cell DNA. Toxicol Appl Pharmacol. 1996;141:319=E2=80=9329. [PubMed]

39.

Barman HK, Takami Y, Ono T. et al. Histone=20 acetyltransferase 1 is dispensable for replication-coupled = chromatin=20 assembly but contributes to recover DNA damages created following=20 replication blockage in vertebrate cells. Biochem Biophys Res Commun. 2006;345:1547=E2=80=9357. [PubMed]

40.

Hirose Y, Katayama M, Stokoe D. et al. The = p38=20 mitogen-activated protein kinase pathway links the DNA mismatch = repair=20 system to the G2 checkpoint and to resistance to chemotherapeutic=20 DNA-methylating agents. Mol Cell = Biol.=20 2003;23:8306=E2=80=9315. [PubMed]

41.

Rao PN. The molecular basis of drug-induced = G2 arrest=20 in mammalian cells. Mol Cell = Biochem.=20 1980;29:47=E2=80=9357. = [PubMed]

42.

Xie CH, Naito A, Mizumachi T. et al. = Mitochondrial=20 regulation of cancer associated nuclear DNA methylation. = Biochem Biophys Res Commun. 2007;364:656=E2=80=9361. [PubMed]

43.

Patra SK, Patra A, Zhao H. et al. DNA = methyltransferase=20 and demethylase in human prostate cancer. Mol Carcinog. 2002;33:163=E2=80=9371. [PubMed]

44.

Nakayama M, Gonzalgo ML, Yegnasubramanian S. = et al.=20 GSTP1 CpG island hypermethylation as a molecular biomarker for = prostate=20 cancer. J Cell Biochem. = 2004;91:540=E2=80=9352. [PubMed]

45.

Hegi ME, Liu L, Herman JG. et al. Correlation = of=20 O6-methylguanine methyltransferase (MGMT) promoter methylation = with=20 clinical outcomes in glioblastoma and clinical strategies to = modulate MGMT=20 activity. J Clin Oncol. = 2008;26:4189=E2=80=9399. [PubMed]

46.

Stupp R, Mason WP, van den Bent MJ. et al. = Radiotherapy=20 plus concomitant and adjuvant temozolomide for glioblastoma. = N Engl J Med. 2005;352:987=E2=80=9396. [PubMed]

47.

Torchilin VP. Drug targeting. Eur J Pharm Sci. 2000;11(Suppl 2):S81=E2=80=93S91. [PubMed]

48.

Braun K, Pipkorn R, Waldeck W. Development = and=20 Characterization of Drug Delivery systems for Targeting Mammalian = Cells=20 and Tissues: A Review. Curr Med = Chem.=20 2005;12:1841=E2=80=9358. [PubMed]

Articles=20 from International = Journal of=20 Medical Sciences are provided here courtesy of =
Ivyspring=20 International Publisher

------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/pmc3_logo_v5.gif R0lGODlhkQBLAMYAAKm5x+v0+IekvHefv+Tp7liXuQBcknmcuoapxDqGrsXP3yhpmrnEzrzL3FqG qgFmmTp1os7W3YWyysPT4Uh4peHn7Oru88TN1ip7p8nS2Rxjl6zB1ejs8d3k6mmStfP6+6zE2Nrg 5kKLsb7I0bbBy9Lm7sfP2HKlwy9tnLnU4pGswaW+0kyCqpvB1bfJ3GWRs9La4A5YkGGcvOLo7a/N 3dvi57nQ3qLD1s7c5pq1y6+8x5+zxLDG2JK4ztXc45e80cLZ5drq8eXq78vg6rXG1HmrxmGOsMne 6WCKrtnf5ZGyy1mKsDVyoMrT4rvGz3Cau9/l68PM1cDJ0k6Stunt8Rdvn2mhv1N9qNfg6dDX39Pe 6n+uyIe40MHL1OTv9XWoxefr76DG2Nbd4+Lu9J+4zRlflNnj68Xe6pexxu7w8dHa59nd6afJ2uvu 8G6Wtufs8OHo8dTb4urt8MvU2+zv9dLc5evu9ezr8maUtwBPiuzx9P///2aZzDNmmczY5Ozw9CwA AAAAkQBLAEAH/oB7goOEhYaHiImKi4yNjo+Qinx+lJWWl5iZmpuclX+foKGio6SlpqeoqaJ8gpOd lVhbVhJee2NAXC1DjEGyWxWvnqqhEHlLG0t5eTkVBG9UFp88ymBCQs/TMXksFRN52hAVMwRg0KPT edXX5qase66YTywe9EYoGgv5GvP19/ooSzy88LAEn74qCaYonFJFgxJNw0BRKebhghMGDJwgURaj TB4kAvIwUZbHDYOQKEg4yHMFwMoFOnRoIAmBBAkUynDmIcGgS4QkFai0a7XpxA8FE04YuCGkQgUw Mno0aFAgT4+mFYRIAOGiiQgDNmZAgTLDBgikCQy0mAExIigL/nA74IEAQYkFKlTe6H3DAS+Hv33x WuDBwwzew9AQBx4wwM/evnBRuYN3yUoCGQVkMDRAgwCBLwkyY66yFMyME1MKqC7wIAEUpxIuiyYN pK3bT1S0LTHBQNuAYi9MqDCiQoWyC8bzSBmhTACDlShGSNEmwAROI8zzqBgRJYKYDmCinZocrLz5 87dD3W3aIUSSJCFqdOhQo379+fjz068RIr78+fz1199/ZAnBznhEVeJBHwzq4aCDDEYo4YQUVtgH hBZ6cEkoZFiIoYUghjjhhxfqMaKJHkpIRijkVaIABSLGKCOIFEywoURIzKjjjjyCiIRQoLR43pBE 3pjekUgm/hlkgkU2OaSSUEY5jJBOFhHaLnsEcYIIJzgpjJRghrnkO5mgwUIZEDiAhANXoLDAFQ6w ecWcdNZp5510rolCGS8QkcltFhRDUkkM4PTCHCO5QYYyGUShDBo5iBRSMUhshIITOJXBhEduuCFS EovmYYIJGcBQwwxAkkLlJUWwsYYWWzyAQQK00npDE2pURasIIiSAwQRNmDGFARj0SusPE7z6FRub AApGBTX4AIMPIXQARQdJZJHBBVF00cUFJkQB7qgZzDFHBuVmQCq65Z5LLrrmqktuFklAIYR4qjKJ yRc0YNHAF0sR4BRUNkxV1VUD93BEV1+FNd8MKQDRxARp/rXQ7JHe5LFCEjAI0CcR3zwRQwxYgKCM BjPFQICgInlaTF15oDCAMmTMoMzGSXSQVapDkenlz68gScUMNcDQaBfiXsDtCBg54bR0F40wghPS Lef000hHIcVFNvFE9QX0QvFGKqsCbbYlYqYNJpUUPtjggx/CXWKEJM5tt4RG/gEihBjyjaLfdP+N YomAB34i4YPXzaK+Zzfuh9qQK1m240BHbnl6k1Pu5eWcT8n4z7063vnoCPpMpAQFbFFLALi0EAAh eqAmQZPpKcEYYyvAhS8oODAmSu+M4QCX7QPYtfsowLuVeSU9bLFFEIIMEQYbQHwQCSFAfLHFDx1w Amgx/k+IcYEyLyTaQTEDbKAMBRSI1MEKeUAwEhEs5OGBSFmAHIPIJGOhDR46SYIYcjaD8PSMMpVQ AQ6ux8BBNOAKf3JLoOx3AQZ0DSdIGMF1kmPBRxkHBQzwSB508BIdjAQJUhiOCjyFAuEoAyPdAQrP VvE5SmAGAzjEQBUewEMe5hCHO+yhrH4oRB8SsQo4sM0wLECAom3rAhmIQBayMAeLYKRrFvRaRqSG kSzypGlTa9rTwrhFE8AgBEE5YFGOkhQDsCENcpBDGqJisDz8AI5y3ArDDDCDNoABDG1IwVkoppaL SfANQpiBOK7BATAQAAo1eM97BAQf/1hLP/q5ln3u/kMfAcmngAcaxfKMghSl3OCRWaEjVazySCgQ QI9eAUsF5lMBs6ClkEq8TTJiQAYEKGMCzXjG8UahDBD8UZimKKY1yhEZydSQElsowR7SsAU3vmEc crBCLTpQlR/IQQiAnMLr7jAsIGAFDH6wHhy+EgZD3gYdZKiity6QqU2VJFSgUkYcYPCoCxghD2WI wLQ24AYmaMMN/MwDGsp1xgqMzZmmu0QPEmCFihZBBAvAgrV+IIKKVlQEGMBBBaAgg4561FdmmM8P MCCBim5BBFWoTQTTw4E6jIQkByjXAmhCgpDk4SQvJIGgUAAdnugkBsVwgA6awwApzOE7BiwdAjX3 /jMkWeCaNYjDHEa1LneRilTmOldY5xABr4JVimU1gdKiEAWwZuE7qCLbM6laJCjBBS98QYxfAqNX vXJAL3z1C2D5qjvPRdQPIIBRjxY7IQqAABOigEKOGEvZyk4ICVCgYUQN1za3va1vnpXb3OrGoLzt TXCgfRviEJe40A7ubqpdrWgZtLjNxna0grNb4XRrotROKG+KjW3hhtvb1qo2tSSqG3FhS4HaTrUJ AoCAZXcEAQE0YaYSIUNwp8tdGVGADDP8w/Lo+iTSmVezDUyvetfL3vZKgg/wja9850vf+tr3vvjN r373y9/++pe+cyUves5LYPEGWMDlKTCBx4vg/mAo+LwMbnAnHmzeCAfjDUoQgQxK+oWzUZh0Fi7K FE4AvQAM4XV78MJLt7C5D3cuxJYoQgG+UAsvpIALXMCSIbRwggIUwQzldQvLlMECMAgTX+i4CzQG Q5IB/GUm8fvLkkmRZMEMU7NTzcQNkEWDAHzgCC2gARCk+QgvsIEGPbiBg28DPmwpww1GgIAKhDAX JaDjBXlYgAsIYLJixCAEvmwfE/qTg5mgwAZwWcFMkpGHkRYolFjeBGa+AAQH0aAIW6ABHOwgBDh4 +tOgDnWohUAHOgDBCiLocC5TMUEmeGCnedgBTjwghpE8AX6iAlkeXLAoJiTjAGVAAZ5RcAE8/i8h CU9YRqQ0UIFI5SELUswZAa78ickJQAVNaAAPQLABHrigAS4AgbjHTe5ym/vc3vbDACAIWQkWgwVo UMEFPxKFWaNBGVJggDKKEzMAkEQARcWJsF/wAjTgmQlZuHcepAY2NIZ3TFl2AxoasIINWLwBCsh4 xnlg8YtrPOPc7vjHQb6CG5jcBUCILnZVMREKehEnEDiANkDSnAN8A6gpGckCXJJnHbCwUNpROAk2 8tOe/CSNpcicBMKwhwAEoARp6aEBwuD0p3+Fh8QCQtWHIEQDVIEGH/BCAMaQgDxgYdWosIALVkAE EyxHXCY4gBEAoAIB7AAAAsC7AwTAE7yj/oEBeN+BDuoub5u4wQFu6JoOBqIDATiHAVGgF9LzdVhL pKYIJ0hAEXlYgBOcAAMGKGIVZHCCLwRRiBiwwhdOsMMioHPlrBZCB8RQ1jnAYIBiMFoXyEg1p0nh 99+6QBeksHupER9pwgf+PIVftShkIA6neni150pKBSilB2nI/hx78O2qbEH7FdgCVybwFRxoPw00 OIsNKuZOVdzlkfdpRiKhwDFoR0CKU8Q/DG4vBh/4QAz7FAf+938AuH/7FwdikHtTlAW31wEz8AbU ZmCVVwmk1EY3wAGeIQeqdDAYSAByAEsNc062REgWg3ZpdxdvYGRLRgUckEhO4RQzoEgv/jgO1lCD QuAZNniDMbiDnhGDMOgMkBZpmlCBpoRKQrCBrDQWr8QVsWQDs6QzI8h+JqgKOKANJIEH4AQZEfgJ ysADutNMo2ABXXgYYChVa1RKAfMaR/gDddQDApMVIAgWM/AwUYhLsBcRyvAEkDQTCJAEhRYziGYD dKEEI2MXeJATL6ACdbEEEGABA5AyA3AXyrABYzEDQsABWzh9E0gJRXAGadAAShEGWPEGMlACarBK PWAaHigCXqAGTdhKBDABY9AB62eH7ZYe6LACRqNWJoBnRhACyZYDuFYHuEYfNBMB95MHRkAECAAB K3A+efAENUAzDAhX0udcm4ABUyAB/lZiAAXgSARgBhiQOlZAGlPwR2BwA6NXBKb3ACeAFVggA7Nw AhpgAFPQfhHhB8qQA40id2QwEkxAcAWncBGgcOqybyNgKeAyMzFwJnkQHPvWVmHzUGaYCSfABSVw BEOQAmVHA+JgBT0wBBrJkXlwSlAgAmwgkkeQAjxkLRXQAxipkWcAejJ1i7fBAcmWBw6AEzHQBSjR BThRd8owAj6FEcqABCoAHRnRHDtwlPqWBwLgBF3wVOCRiTAmYTbpFlRQAUkwHG4AAOMSd0iQeCTQ eFFplhakA0+ABAewA9d2RR6ABADgloLneDpgdFAlV5uIlUFzJBYge7QXLmylNOEC/nzEt1bBB3fc 4i3ztC7MNzVUgzSlgkYcoJdZxpd9eSRU0BTRsoAM6AP7ZIDT0n8C2H8JKC0wMEX7l4AKaH8MKIA5 kxWZKIGXiZnekyR34UgzSAA6uIPj4BnAyZu9CYM0SAA+uJu8iUyWaZtB5mJlGCZl0wQH0F06cgDX lZV/YAHaRZ3cGSLfNUxU0gDS1Z06AgENkDdUMFnkuZ4W8iPYWAmcBVuWRVp4gzagsF0SQp/UmVyv JSIk0lwQZwn5yZ/HZThxk1tuQ1qm5SHFdVwIalyjZaCvpVwNilsT8p6UwKDyiVwQylkKap+fcFq8 NaIH6qAmGp+3JTeKE6CVMJ2fXHWgMLpbqzWiEnIAedMhAxqjgZOgEApaPJqjPzqjd7MiLFoJDYCf 7EkhFHCeefMHkpWkUMogmCWEzJlgLsY5V8mcV4qlB1alILqlkDMZ/zWmZFqmZnqmaApfexAIADs= ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/logo-ijmedsci.gif R0lGODlh9AFLAOYAAKNFRUWGyv8Amf9wxkRfpYqtyNqcofbm5qWChUPK3aWWov8wrODLy3/T9dhM TEC12XKUqD9ZkeR/gN28yWvL8sTN31WIz8O7yUGXuq2z0bPP5Une59fb+syZmcBmZsB+gNNxct2u rle66P///7VucUSlzaVXV33V/61sbX/D5FWq1m7W/1PL6qmptv9gv9vQ2P8fpUGCuKZqa+aQkH2e uv+/5cGOjlDf+f+f2aLX8UjK/2jl/UWc0dZkZPv29vC0tF2Zt3qu32u64p682mypzbtGRsFXV0W7 66iLkcXc///f8pPb/s6vuWqS1saaoqy/08ensvfa2v9As0jF95rT70Rtq+ugoVfP/0Su2WbM/42k t5KPpk3x+bmXo+FwcESU0ZG+5bLZ+/TKytdaWt64uJbS71SDuECxuLaAgpKy28fV872puGr0/dN/ gbRXV2Wq30pxwZquysHC2sNzddnk/9SPj37i/1bJ9+va2vjv72y87P+AzFWc1oSLpq3D3////yH5 BAUUAH8ALAAAAAD0AUsAAAf/gH+Cg4SFhoeIiYqLjI2Oj5CRkpOUlZaXmJmam5ydnp+goaKjpKWm p6ipqqusra6vsLGys7S1tqV5P1YHt7Y+UWIHI72EIwe8qCNWEruEBz/IxJ7G0aMjeXnD0tuNYhIT FxLRVj1eYtyoUTMhZAZeUbe/PzNebWPJuhVkEjOCPxJQ6mhDV0kePXujfMxjNqNHj34EIwoSMyOH nR3hRviQIGGIkzYSRx2wouHEijstivioZWXGjwlraJgpcsqHlQllGqxoIG6GgRQiPKwMGanlDwYv cqSgGUodgxxsorJpAKIa0VsjfvywuKOrBG8GWLD4QOYqKCsvlpygIAKLjQm1/yRcSNOkiZkqTEn5 mEGmAQUKd+4Y8MmWSF6zjSS8SJIkB5gghzuJsZLEjh2pXDbYCIG41wwrSy52xeilDosHWtx09kRy LQssWJBwpiU3iN0qZoyYEmNAjx4RwO9c6DFEhAoFc1YnXhymTIoCuj9FoWw5auYNCWQrr+XlQtcb 4G8MGSPkQQkSZR0ZE6OLn1Vu69vPqCYmxNq2Kty8fyW3LhwCfURHShQOdRAHFkccscYYbZ3HwHaL KNbYYy0IyMkIM1R2GRt1tFFAAgnoB+EsP3hhwAo3bLABC23YkMADNKiGyAgDTWTFURO8MAFEmfiQ x1CJ0GjJZGRMMIEcF/D4h/8yVjwRRwtudNCJkJZ4kcFtAHqAig8GGGGDCgWM0QYWJQABQI9AQuJj modQWYkXL4ThWBBaaOmJQtWxwUUbdRRBghYfjFjLDCCIBV0RBZiHhpR/jMTRDzZ5IWkzfxzFGGMT lOPFDNpEKilHLuWxJD38uBRFiTOQioyjEkBqhaReUErIRl7w80MUbB6llknDSTrDSiNMB8IcbhQx 26zzpKpsqtXksUyrnsb6Hq224mqIlVj2YeeWbfQwRg9dYIEBEiQYotCyqbonyDWTSVCrBCOwp8sM HEWBYa2p3oqqqoKw6iqssg5Crals/gGnnGAQUWck56KrriA2bahnG0Z4UAT/ACQULGgrGM5hgxFd mgeEG3jUUSsZFeTAUQhUnKDBPvBYwUASYdRcgZGZDhPFV0mo8cLPE+zzQx4SVFDBBUbyU8YKTLv0 qgQhyFFGrSEs7QcT7xCy8wRLaHABGQ1tOpTMdpyQRRYpDKG2F8P4QFEPcyiARHKEUDSBBn5cwMTe THz1h038kHHBEFSn8UYGUGQ9yM5kpJHBBSE09JCognhR110EzM0KHmKMUUAJGJiARyF2a+A1GXz7 /QczIRxJxQrv8EXG7EhasZEfeSc9w9JN60K11FTncIIcWMOz+DccvMDAPA7NQLnBNDtGBHKQlO71 BHybMwhFG2ZWQAFahI/C/34bt9KhD3XYADoSNswRggaWWUYG7yuc4LIXB0igBs1hmG66HD2wiRXw QIdL1eyATtuV/bzwBMAEJnhMY1rVVnC2s4GhB9qgSAXsF0GmlQFrB8jDDEpykjsk6AhBeAg/QnCB FByhBJpbl1Y00ADf2FAPF/zBH/jihxTYMASGe4MQ3xAHDE5kBnIIgm3q0gQL0MAJYzCe5bCEgECx IgogEEEJtiAjGf6Ahn+hQAXL0AMdrs5+HKTCV07UwSQdgI0RZKAD7wDBCLIMjfbzgxH/QJHFXCoJ HAhkCKJYOZpRIQVEQIIVGZGVL1pmBaPZQQPGYAVBEA0qesIOiM7ASQBorP98rzCCFkBngjz0wA/x i6AfKli/E9BjAgekgtriEAco8MkKdMhlz9RwwCUsQQ6bQuNfnAAc2BSxB0/oINP8cIVmOrMO8NBF SUwSQWdeIUnfsF8W2kKmEtSpDWBgWhZMCEO6ZWUCOWiAEOKgAhUABzhgcIkE/HBDIWZAiHzIJx/a EE0rZECJTLSAQC0ABwUYcYqYQ4ANWmEFJmiRBHCRITr9Eod3BuYKKXDJRqjJNDdKwJpXYMIM1OHM wBCTm8dMpjL9EEE0jrRSVtjfHxkTSA6Q4aDRSxj7GnFOi1CgomIJTwpAEIKNMEAqKUoAJzm5hXKB khYH6EECtlguEMDPDhH/NMAYUtDMLNQPay+ogJyGkAYbAAAAJAMBAXVJBi/A0pe/7IEE7EcBPahg lCXIqw20OgSQapWr1oQCNCQwzRVc4AIgbSY95LBKciLhrG7wABQCQ1nzIAEkf5DZEtQZBze4IVwI gqeknqCHIb5Bq0HQZz6dMNh/2mYNaxgoHGYLBxDAA6FVIAACGKWKEcxTBKkhhK4o6tkuHGEKU2hm CmJXzSsYYGhjACkUZiCGOjTzDm2hQV71yle/brWC9mPCYHlZMyNdqqZqsC30EJZI3ipCV3b4aXFZ EJ4NCAFkBrADJrFzBiTI4L8AeMFTaWGFsJRABg/yAvyqOQYJrKGrZxtM/w/kQAUqpKEANnDCICSw VsZ8ZgwagOsaetCGv9hVBRjYggmQgAH9GCEOd7Bmg9eggxojl7UzYEI1ZzAGK9W4xleYLjKxSyYk aPgPdXAACNpQ2Qdc9g/TSScFjmMDPHjACbB5pzsyAJx2qqDBXfiCmMXcgXlAgYlNkMC3FEDb2W5m dZfLLXpYMZIGiIAsi9vKfRRQ5SsjN7nObUkWrMlPHzjgxzWerhjagNwjkCnFK27xAV4cY2fOuIJZ aMBz+XLAMPDYrTRVgxo6wBkJ5JQIc15ElOMrAj5b2Qn1TcAH6uABEBggk0qVQRdeIIwBgyJ/SmKk BJ4AXBMIgrDNdcAP2v+gg8D8pQ2du0AZwHBhEkBhwx1OgpodIG3nOGHJfzFOCSBgAiagwA2BGgOM nakDZTNbB1NIELS3WukrtOEHY3AConUABSuMYQjxJpO1B6GR6F7BsckpWgPsrAI0XNsH5HmnCKCg bhXABjbKBsGYAxCAedNgoBa49xhs0OYq7HUEuCUACUZHCo34KArAQMtPi+ABI4BgL2mxMxYc/rcx zPEOUJBAHQLz4x4cwNCInkIXJECGNpyQTEAo97nTve5mtnvZzTTxvP2QgxzUrFVjMMAu1VABAxgA 5YZE5MoZMYMXWOY0PPdBDygAHhApwAB8vHVmlIqCiPr6E3upQAisUCP/RRxgBlNOtYKZZnUHRGEM yAXOG+ZwgCKkAAzULgAaFlo5Al7qsBfAfBrWYIQ6zME34iZXIYjD7nY/vtEPeMAc8FCE4/65Wz34 caO70KcExb4Em1/9EALzwi3MQe4LZwsMrcjA37SzAw4oAA94MGbHj0HMAYhBDGZfBI57HwQOKXkV kFAHuQsUDnIm3yLYNS96uQtW8Ie/AaxghRAwgApCaEH4WmB0L9C1LQrAfI1lQh/BaH82BSAgBkhn Y0fQBW1ABnPwdDDkVIPAelbnemMQGEKwgdwHBmVQBl0nAeXAGKKmBnLQAeXXAzVzSKimfusiAY90 GgFYORqwAzfwItrB/xu4dgZ993efoAxkwAZ28BmO8ANkQAFacCaVw1IrcAU15ngOkCDtZCZ5UARB IHpp0AIAMBtwwgGMEQZIsgZO8AFGUARzAIEb2GUK4AY28CCCYIE/BoUJ0k0AUHkPYHtTAEUiMAV7 GG8PEIBFcHFkQgNbSAj/Fhhk0gcokAdG8BcmhAVEYARwMU8nxgM1pwXTl4lQ+AXZFwNVUIdFEAPe FwA2MAbip1s2wIi0RQAq54aO4Db0Un97cwEZUIu2mAFPMAQ3ZENhRAFCgGIQsAUekIJnY0IPEImT qAGAcQQPMIwReEIN2AMh4ACNxozIAYGxl41r2IYV2FdO+IRR4ADYNf+FoJgCKfCBOaBVpmM0FSAH GWADqWgEXeccqOaKiOADXsB4LJAAyLg6NXgaPDg6FLGDqeaDnKALUsEG/PBJBLc7QmBkg+AFzNRM yOUAYhCBWKACQAABngQAVyh6cdAFNWcwflQzOeAERZCSbvBYDDAHb/BOGSk3IvIHFvhnFomRoGMm PhCI0NgFLXAENlAAvudkZlUCgrhFFtONiFgCfWBsRpACJuRoWFAAcuUFYPCLXxAgRkADYyZmN9mJ VfCJOxkDbWYDbPYBfRCWBBABClWFYZlbuuUGbcCQg5ALVkAGSRQEREAEptWXptVOtLQGe2MA7PRY JkACbkhv8ZYgVOn/LmXAFliQGth4hwkiAkZgBD85h+XEACSABdn4ACqwBUgwkzVZkWKQRVPIkTv5 kR/oBFDgB3VwARrgjnHAPlVYYWCASKM5l4rgBWVAkSDSmL5JAUpFbke0gwhwLAbZIzOwBAm5A22Q gIpQHxRQACYAJF7gjY1mLHMAdUDQB2fiBi2AeWAwBLTUAlqyDl+IN2DwJApAA0iABgfgBkPUTnkV dchAHIGxnSHQnaCDAeD5B0WgAieUjTZQBNmYV+xjAtp1cffZRT0wTo4GoMZWBx0whxcnBGtAmChm Bm7AAG7QB135BdypfWEZoEVgBuL3AUWglmupUAKalqw4o2hAN4ng/xRDAFBAYAY82qNmAAThowBd YAMfQCwVAwKfQSjjBgDPc2wdsJgnpAcXYABDoAJl8qHzCRufqQVE8Jl51VTzaZQOWiYmkJ/Ddwf8 OQdTCARbcCZFkAaXR55DcKC4U4tasFNF8ATTppdEQAM1qgg+gaZTACIJQAFTWqVnEHVuqA47iAR4 t5yaMBKYwQWU2gIg4AU/UHiCgERCgAZHVjnDV41F0AZI8J8QgABo8Ach4AFpAJJaEHxR4AWihjdk VQA0QAMKwKR/4AYK4GVWOi6LlJ1o6nujWqoYgAFmgKp/YASJko0q4AEsCht5NS42AAUoYHHSigFo EKxZ8Bqgw5F/0/8DXyKIGakCPACgMrBQIYp9HFcEH4AEnphbymoEfWCiYQmtRTCjEcCWC+Ux+rqv JGCjhzAdcvAYb2ABENAHokkuJGAxkQWtHUAGDNBrELNsBYABCPCpAiOuIvCZR9BlTJmugmAECkCu JTA92wU6irirJeugwBqRoUqspFomGzmv40ltaRAH+GqLLSCa/eoEmKeXG/mniYCPNiAChAoiYqEC Z9AHIisIjJpU/aWxkGoJGBKElJq1lHoBddBgYjAQItQAcYACaUIcLDCUReAGW4ABQIAEJoAG2tAG HtACF3an11k5dSAHavM9t8qSgoAHRtAFRPCr+FmBcTCUD5C2a9v/tm87DCDQAr8HBB5gAyMAANN6 rBn7Bx/gAVrwaG47FCPQA9j1nxighAcAAiSbV5kIoChgAmQwDPTKcdoXA4oblgjQuH8AAgpgomYw uZXLivvKlhoGuFsAvBEgA4uECBJQsEGQAXVgBJ5FAtU6AXhAl3+QC3wBBirQlBpzuiR7lEzZuq8r CAxAslZaJmiAMaQLATtVvr06rYX7hofLjLGXtgrAtm4Lt7m7BilwYTpLuQBwnj2buYC7BmmwlxCA vIzgvZD7mWegBTJQbgOhDjugSf3FeVWLCVGVA1rbwQ0QDnJ1KzMwAZ3KBKu3Bi0wB3OQkh8AAGxq AjLAcoNABhXT/wVdUEoC87wf4ARdEJ+HWQ0H0AY0RwIk8LRviMIqzMIurGIxPAi09wEKkBpS4gNu wKZIgAIAgMN/QMMeoAAKoMU9F5JXLAMAkLx40ANGgAZIQANNVW5A0sXIQQIX08JmwMQy/MRIwEVT 7AZm0AcIgMVaLAZp3AcEIAPudQgjoURxMAZjUAcMYL0acSr0whcakAJCAAQykB6IcMZpHMVtzARs YmV+Mpo2QAZq/MdntYj9IsQeQMRGTJNIvMLuCgDBCMN37K4+GSV/I55DCsiUI8g20AI0YMiPwMlo EMVa0LqgXAhRUAdS21/Jm8FD0gM70MHW/MFMYABtkAItQLakI/8BBkAG1fs3WYwCAtYmDNAGHyDD dTkBHWADEdukxXAAeMAA47w94CzOK+ED5XzOhJAHEDgHrmgxHtAB90xwDPAB61wMdQA3EUs+edCf HuAByikITRex48zPJmDOhgDQKjzQNGfQbMIl0FvRhzAZQfAGfNAEASjL3/IuHBHTtXKXE+AHC6cH lxyfjRDRczDRJj0rDEAGvOADHTAHHfDIbULP9pwmYKHP5LzR/lyXAQ3SBX3QENMlbvDTi8DTPo0I UdAG/PWdxCzNmUAoKnLWG5C14QEeYkEEJhDVioANtiDXnUHXqkA0+MSJ3scHBRAHtvgEgP0EYLCL vvEGGulf1jv/1/K8DafbAjZgAgAgA06w2GQ9CXsBAimA1pqtIgApA9dW2aBdCADBBxYwimLGB31J 2H+JuTKQ2KGtCRthay742pHwA0XQBUmb20p1BspK269NIC0wihz3BfrkZfXpZaubwCRA2b7d3IyN ukGZ2w+QqKjq2s49YAfgAF1gBsI93F2Zied6rMj6WJ993eZNEAfwvJ1MBJyEyfp73pWdBxSjAGYw u/Z93/a9BQgAAGjA3PD937bwRg6LBm3QKtbyCMHSEszwCm5jPOsyGQrICj4iEu7HD/7NU+yhgKc5 ylvQB30AAbObsH2ABFcMAB6wzACe4hFxeBILNrXi4DNCEcyA/zpy0Crr9yOb4DYKLnR1cA6N8hkh wATSqKk/+Az04gXqJR2fQQZ+kIsU5+OScHiyOOQAbXo1VywqGVkf0AEvQOQq/uW3cHhuJxV2IOTO 0ybz8ANpgUcXcA+GkODuQg8XDgkvEVZLsAIU4AR4J0IbREFDpcmhYBTgEAdN4ARabbW68AI+hHoi 0AJjMNuIPAN9jjYgAOhgfumdsWqRNBpQBOONciMWgVURtHBG5wzLcCPMEQISoAkx5Uv38WYvUTYS yn+kgERBaxdnOCVH8RgpLUTvxHuScBOybkK0junGbhY2UQENkNkbsNbg4ejRoEELZ9OY9hcoCLWp IgYcoEs04/8HYzDnjtDq94EFAp1ZDGASgYEa2xIKSJQGtkFQ5X6QE/AYRAAEQJCJsBGJXp4IN4Hu d6Duxx7wEqEML9AAHWAEH1AAKuLsa8A2fDRCvsh/GRAYZ0MBKZABUcQRDFBTgcQ/VNABmHUJrX4S jrZ2k3Hnj4gGjyoKSKREFnAXa7cJ0/EYfCA3SNAH956JRgDupAMaJL9zKy/wQk8MRtgAa5AxZFAE LdDszg5t/zAEv6gAHtAGTkBZJrYUPcAE/sMEIFABooYwQxAZkHAN2RBTWHUaJeABlNMSgxMHKrzY NLLvktDyt1EFbmDdjRB4KW0GAGADaFAsaEAE06f2b+4mhsD/9ub59qcQ90Pf+I0wEkoxPn+rbs5+ A0/QAyBQHMdx9xPAZBT/FylQBxmgNhmwuRT99Y4BBh/gilkBKzFNXWziLDeSKhu0TWTiSYPgKCBg MSH/N//wfr7ytW/+NJ8RDJoqAf+EJUqoCUZoyXxgJgJjAB7QBSUQGYAD/Jsi/HW5DLs/qsXwDzDN D9ovMPMgNt7wKVAOMc8Cf9RVI63/KaAS4YVweBwRf58C6Y4vKMqg7C2QvCHQBoBwIzh4M1bwULJl cvCXN3aXFUlBkZKSVqCF8vFHBqKmFpYDBrYG8vcXJRGydKKh4SfHZCARdfonNsOwtJuztHJ3hFUC MHI6EmXV/2OERlNki0zGerLS4HchIZFn+3egCmYtK9Hj9eNjK5HRZGFWRQCwDR8vD+8j4Rf0xhfg FrKd12PDybYoM6KdmFbtmgRzf44lW9bM1oGCrFzBClfLxw9sISZosCJhhpwlOeRY8cKQ4A86LOlw eDEBmzZUEn5UdBXLgJdap/JYsfLCjh02OVy9GlKHzLylTJs6fQo1qtSpVKtavTrQip0NaBhs8zEG DKEbUw6VgGACj60xVyJlmZQiSAEaKNCYA1shTKgyYIY48Cmhwq5pK1a49YNyxI8ZGg4SXnEFmDBn dbxIsMIEjLASzhRbUSOtcJY7pGcVQ5WrQQM9rN+4btFGwv9pL+kswKlSxRnWbWJCBBHyhscXGkbG 1IziY0Qehp7VCBXtNouBGSAvZz5SgvMfjVYEOy4s+kkPHzNCNHbs8eCuXWSsjLAyA09LlxyS6J2l cYb3x+CHjDEnBlBCsUFggWxwwUUPjOzGYIMOPghhhAx2t0MCRZx2DhOETJEAIhjIAMU2PQzhFgV6 BBEEDUigsI0q9oVBRYw9/NQLKw1QkcUVOupogBiLUXFQGWVEouMUwQzDQBtDUGDYHZs542Mv04x2 hwhWWlmHGLcwphprerjmGh98tDHDKbSpc1sfbjyIGXDB8QBnAVBM54UXPcygTZTPUXmllW204Ydo Tma3ZpT/g93oFml3dCCGF4GCV5gfDai3HjmfJUEfB2oYFWMd1NVIDY47XsECo3nMkMOAS2hAIIII pqCbhLLOSmuttjKVhwRsbFDAmvBYEcIOg3RYAgYrwuMoeBQIkaIWJsx0Ci4vxkhFG15MMNgKfoxh AAWjQgESFeAxYRwUFBj5ACIAkNCFCIoOqt0ML0gzWgsqqJBddi3gKYEGXWaQAZj58PFFE7qdaVsV arLJBJhwwnmll0MwkY2AdjRpL775eoAGC+9uZsQfQGW7bbfABNNFCCO6peMFYzCxAqVLWDZBEjYn oQYTT2QQRxwFpFEKtqys4J/JJ6dsBRlC7cC0BGM44EUb/x200EUbt16NddZaT/VDCLsWYASGp/xg ANM3bNDhGUAsguyjJgpBBA1odEDPGKDsVYYEXsjhWBZr6O2EDoLrEBsT387gBQhTGCkMBgCgAYAH IAxBGiIlhMzYQaMdMYcbQGAARB8KfGCAFRN0qQcUY4zRwcBffBGAEeZ4EQSaCnvwYCphPsxDn1aS dk3mTXLuOeh9IOFGER4oWXl2IXc39Ap/e+HEEZaT8IIHcYx6xWVjFEbpGF68cLMacnSuRfoKdGFD DyNpPr0T6JZAAh4g+MH0Dq4+AcWfbcwxhyIYQS1bK6ABD1irGTCBC7wyQhGK0ANbYMZsaTsDAgQC D3sUZv9ZRCCCFgDAkG1cSy8wqtYYnqC5LEDBAQ5ow+IWtzrKKaoLIBiDEI5gPQ+9wwc+GBFpjoS5 xvxCBFhwAwkQgAAAmOADDBiBF5ZkIhE4YQYzcAAf4PS6AMyBEbSzHRLm8KARSGANYnrdF3iABSz4 zl06CdTminjEJC6RDMvxoWSwgLkKXAwyK3QACIKBAQyYwAceGMKoCBcFB5AoC6opwxh6cAG9qKEC TzAiEgEgAyaCgG/TuEIf/2i5QYLgCfm7gatOuYFUKsADIUSgK18Jy6hI4AIMTIAtiSNBJlDwAaAD YTw0uAIOqogE8gCWXnIgpDaMIQOTyJEe0pCGIOCQCDb/AEERjvDCI3ShCC3AofWy4zhb2DEYWHBG v4aHBRDi4QXImsSVWtADB9DAjLCLwRzU0sWEIcFqD3KEDej5ujRiwZtHEEEHRlQk7KiTnfAYZxqD 2MkrPLMAQUAEEI41uRxdQXAgiMIy30KJIRjBCBcwigYysNAWeceZl6joAy5KTAPokmmndFUq0ZaA e8Zypzzt6SmsAIVaJmALAOjHKSQgB6axIAFnwAACQhSPZAUTbkBAgVfigYtjliEFNcyAHihAGj1Q jX0eeCAZivAAbz6gC2jAghbSla5AvuMUPkTXAy50vxwBowRusAFD7FeHP3iBNVZyaxEUANAAxKB+ fwDB/xu8OAexLSUPyHGKD9rgASTQIAABMKNAhUGEkcaBNFNIV1//Kjm6Us6uF2JMYTYqgrHagARK VEpeizQFEIhhDHHwUhBaMNI1DMEPxM3AaU+BhzbApwKa08EdZOuB2jYCkoSw6U1tmQDG+nS73N1a HhxgA0yggQQLMlMOhNUhDEDAl1F1G1UHKQ+w6IUKYICVB1ogBCFY6QgFGMMDi0ACJKyhCESA6wMU QINmfLZYc/1DXXPogTyAIAOkDQYNaGuEHoyhfw4mrAh4oAUFBIAGiK3nYtXSgybYTk0emEBTJnKS y0BrHsl1oAc+oADeBXJu2lscDrFwYQCM1AhdAKODV//74wjX4QJUWhzYHggAFAhYsH7ALecY4IA4 5BduRfaAcInrhwysAcM96AEZSneBadzByQ4sQpSnjIoydwAKPiuAnbFryzPAt7t87jOt8mAAZdSh lT7wglKZ6lQbzMNRb6EqUZfSgwqIIg0tcEMdbOCaK6VLCzQAwtrwUAQtCLRYaAEADUYtyJk8WBj1 q0MXsPnj7KhACwWgJt16kIbC8iCQW3ADEjir2CqggBEgiAMfbHMbAiCvvPL4gRVUvAadkKOV8hgB HkJgBBvAKZB9kIEPLq1Wy81aC0RAQ2CPvOYc3tMAThABQdOVYCCYIS2CNeTJsDCHCRShAG/oIBGQ YIP/gKdhuMUF2BouMIQOGCAEIZjEyTbd6U+fYgZQuEAd4vnfIqDhAWfouAJY5OeQi9xWuEAvL9c2 YxFOAjhEAMIWZLCU8WngEkjoAAPcQIR7qSCN4MQAChTtBlGDUxEMCDWqUcDQEfkYCz6fAB6McMMc 5is7CnDD7OJAxF3HAHmZjYHXcYMCtVjBABZIGAEIgAA3pPxXTFBH2S3QgovTQrLxMEAddq1eE7Dz 6VFP19RLUHWGKJ1x9JtA9lRg4J5/SNH1vjf9QlCEe3l6C1bFgxviQPAw88xnXfCAtUGQAivBtViB lAHjRzAGCpwNp9jteMeJSsCRy372DaL4DdKGAUXM/8OJehCB5IGgAGLOoyAamMuz/vABD9BAY6SH gAyE3wE0DB0AXgk6zwN5wVOMIQ2x9jkT/oDtFvgdnBcd9sSdgAXhxAABKMhD12OAmyrIQC158EIX 4JDsJMZ+HmKQAA3e/nZNAAV1Ug7zcABeYGx5B1XgZwTiZznFUn7ltX3dhwLfl3xEsBmBpF4yAHKC FQexRj+z5Wk0kERQUAzY5gQ7AzBxkD4rsiB1AAIYmC+B5Hwd2ENrsFTYxXGutwUIQG+0B4RBSBVe 8AQFoAArYgIAgEHx0EMsiARogAJJeFXNRgbF93Gn4AMd4AYfgARdiAQyoIS2QEhugAZI8IMeQG5H SP8CUqh9cdAFbLWGbPMHDDBSc9CFUAgANgAtB+AAONYHmmAORrAFx0MCYIgCDHEAYzAHW1AF7Edt 8/ADPdAH+BcAbycmcXBxePIVi3EBLacILrYNdGgEdviEKJCHM8Zbb/gBccgI37YMXviFYXgOa9AC q+gGAGBEmuWDHdBKojgHHWADeKiHYmgARsCFXgiGS3gKUdAGDnBjCnCESIAAYCgDTPCIQoiN2QgP kXhjNrd28BACAGQDZPAC37gNP0AGflAAKACKWMgAdmcDHcBQ8JAHZBAC5UUGHuABc2AADDBjPwAC bVAHIeCP8ZAHExACBkAGeEB3PtAJHmAAttAGAvT/AUywdiOQjwBmjs3mAApAiZxlAWLCB0FgAMbh IzMgAWQwBC2HBACwf/6AkArJkPEAkAJJkCnnA+94aU4wj7YgBgK5kDMRAm7wc+Z4kAm5kHS3HToZ ED0ZD9cGjB9gAyEwk9polVd5FQfJANe4DSNwAAEyAwYwBC2wZ1gJIR71AWYAB8DWWSL5BlAQlkwQ BB2kBTKABhv5SjxklnuZNTWgBHxZFRLQAR1gBCAQEtTxE1SEDV5gBT/AABXgB3GABgsImA0iYUbQ B14XA8D2BSLpmVuABjIwhZVJmjy1B1IgAKkpADUAIT6wAKnpAqUJFV7QAlbyBLHABGSgm2RgeC+g /ynm8wRr8HxKKZtVcVZoYAaayZacZQYfBwDfV5zRCUs+oJqrCSE1UJ3SyRRW0G4iMAmNJCQmJQcA 4wQoYFXaaZl1oHFbkJya2YMmwI7oKZ8HVJ2sCSEDkJo4MJ/xcABl5gRaxixBAE0DlwFUAzkf8JL7 aRV5EAJlZUSm6AZOgJcKSqEQUp8VejUHUAdldWNvyD6ds4VNhKEP4gMHsBwjiqK0cqH7WZ0t6qIv CqMxKqMzSqM1aqM3iqM5qqM7yqM96qM/CqRBKqQxags1IAVHeqR/gAOoKQALoJ9/YKSpCQN7EA9K MAAwsABY+qTboAQuAAMCIAUuQJ2qaZ+ngAMLsP8AqOkCAyAF8GCkMICaC7AHDGGkSNqmTrGkYIql e/CXtqAEdioFf7kHXwoDfRqlYAqmdrqltjCkjeqojwqpkSqpk0qplWqpqbkNe1CdYaqpqnmaUtCp qUmltoADqdmmPvClUhBCpZqa5vCnK/oH+HmnPuACYLoNtSoAf4mfTcoQrIqpTOEDTNqnuLqoSlCf uCqqf4CrMGAOoToAe1CmjHqp00qt1Wqt14qt2dqj24CdqvmkvioA36qaC1CkqjmsyfoHxpqaA1Cu ZHoK6roAfaqsd6qspnoK3SoAo4qvAtAUTEqv6mqd0pqaaVoDr5mrvhqb6Tqu84CjcPqllnqkLyr/ BQZLoxFbrRMLo1LwsD6apht7ow6rrZVqsSFLqdyanfd6slCashRrC6F6CsgarSu6ry7wlz6gr56K hQZrn/vKFPiasKegmjCwDZuKhTVgDkyarwIbsPAQozhQA/u6ByMQqjs6pci6qaepmiMwAi4qBSOw rzHatVtLrV37taYqtS8KAziQHF67qzBaAyOAtDcatZoKqnFLskKqtTJatXfroyarmu36qyr7twrr qXuAtan5lxsbs+56ChQLmyGErKN6r/LKs0sRuUNrrkorubaAtJJbnfKKuS+qtSMQuWfbo2T7onOb tWLbohhboyN7qajLtaZbncw6AjiwB2pbtvUJ/7c6CrKqy7dDCruzu7vBW6N+G7iVK7i/uq9P67xP aw6w+gewqgSOm5r2ibT0Gg/KKw+dG7pLK70oC5vvqpra+73VOQCji69Ri7tPS7ED8LQ48LAuMKgC sLc4MAJKYLi1+7Y1sAe1qrUL8LTL+r+w6bxtK6WG66zx+7B1K6qdargw4AK1argCXAPL6rRPu6uy 27q066leW5216sD52qlv6wJOK79geprQKr8u4L6mepow0L8FHMLOe6Zcu8I10MIvLAAuHL8GW7cs /LD7q8JM6sM10Lbwq8OvGcETTMKwuQdOqsNfir/6O7XGe7yAy6/im7wnu6+g+72Le73wkMKf+/8H ccuV3BsP3qu08hq+XKwEtPq4DPuiSnC7WjvEWvu0I4CquZq/dtzHb4uaqDu6eVu+hYydhay1gwzC UasEfsm6ZmvIdqwEgPylwGvIWmvHiazIjLzHZ8vBm+rB66rJh5uvpmvIb+sDkIydUVvIdqzJoiq1 YavHLeqXkNzH1enKowvL+Xu9j2zJp4zIqWnIquvIkIy4+fu2mqrJIJzKfMzKAqDIWIyjyLvFy3vN yku0XHq0OKu09lnJpLqxVDq1m2vN29C+LevNQDu47DzG8vCndsqnTIG2eGzHuAq8JuwCIHzKpSrI YArCofzBoYrHqwnKILzMX2q1q9vD/My+p9z/qZlMuhhb0MtcnXIa0PzcwVeczLzMxKgstv8sAMkx pbcrAOmrBFhazGcLvC3awHZstw+N0iotti/duw+9ABIty5qa0D3c0CltqtI80a/5zExK0gJNzTR6 zlyczSlrtT9rpGZavmIoswvQSsS6HS0quTjwpMrLxrlMr+sbxvKgqYvqFKnLx3zq0KY7t8CLuv+M ukgN0Qw916i7yzYrulvr1o0M0sQcyStdwsMs113L0bCJA7BsrJgc0r1r0KB60N0K2HPtojRbyDH9 2H4Nm718030t1DstzGkt2XSN2Y19vXAr10lNpFqs2lLdzq7ZumgKud4KpXFLsyobr+VKrkxt/78a q6pMzRDbTLgjfQqd+rNZzbh+KwXP+7T07KKaXdDAi78DkL6sus/YCdcZvbstHdmyC6pvOwLW29nT DZt8HdFia8ijrbr4O6hxrdGizNEaq5r7rNecLdJ2jNF0y8+R3dJBm7+oKdIDDdCQvbUw0N+krdjo bbrdHcDiXZ3n3dmk7cdp2t6oPaNF6rGBWgMX/sit26dyHMLUNrWqaqr0+5fY+Zpyip9iyqVxO6UW vqmCetzpWqt766QrftHR+geFHbQ47s7jWtB+jJ/sKwXpOwIwQOC0Stm1+rb6278AjeRa3d+oud0I vaSB+t0umrdHPsH3fNJpjb/m/ddiq7pvu/+k+Iudgz3K+eoDVd7k6WuzX17abFrFdZ3fYs7SUS7K XUrZlo3fAg7Qeg7Tkm3IyeG/dszTVW7fWg6qzBzmcS4Fc961T07hFS4rj8zj3OqX78qEDGHpS7HK mQ4Vj8yVls6VTRGsM8rjLjrn+enLjqy1Hi6mo8uqqqrH/NzLLr22nOzZb13IhW3Isa61vgrL3j3a CK6pwN7kaM7RwB7sDzvsz4zYH93nxm6/uW7LmhzounzZD+7dlbzZ5U3K0Hy23q21xL22I4CfDv7M a1u9HR3Jk/6iKRoheL3oCnyl6Hq+Ngqymwrfm+qxA+u6rdvvNAqnAx+0OR3JR/rvAa+jBi9/o4QN o2nq8Ax/0Xabowrvomj6oxqv7w5f8Avv8C8qyMObpuAN7ykr7w1Sq+wqD69p1tN78jsq68EL8TFv 8zL63zefxSnfIPhp1VXaw/Kg8zj6rAtNsiE/9DdPv/+e9DDK8w8SxSpsuAOQpi/f402P9Vmv9Vvf ok8fIZYO6ksRCAA7 ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif R0lGODlhBQAKAPcAAAAAAIAAAACAAICAAAAAgIAAgACAgMDAwMDcwKbK8EAgAGAgAIAgAKAgAMAg AOAgAABAACBAAEBAAGBAAIBAAKBAAMBAAOBAAABgACBgAEBgAGBgAIBgAKBgAMBgAOBgAACAACCA AECAAGCAAICAAKCAAMCAAOCAAACgACCgAECgAGCgAICgAKCgAMCgAOCgAADAACDAAEDAAGDAAIDA AKDAAMDAAODAAADgACDgAEDgAGDgAIDgAKDgAMDgAODgAAAAQCAAQEAAQGAAQIAAQKAAQMAAQOAA QAAgQCAgQEAgQGAgQIAgQKAgQMAgQOAgQABAQCBAQEBAQGBAQIBAQKBAQMBAQOBAQABgQCBgQEBg QGBgQIBgQKBgQMBgQOBgQACAQCCAQECAQGCAQICAQKCAQMCAQOCAQACgQCCgQECgQGCgQICgQKCg QMCgQOCgQADAQCDAQEDAQGDAQIDAQKDAQMDAQODAQADgQCDgQEDgQGDgQIDgQKDgQMDgQODgQAAA gCAAgEAAgGAAgIAAgKAAgMAAgOAAgAAggCAggEAggGAggIAggKAggMAggOAggABAgCBAgEBAgGBA gIBAgKBAgMBAgOBAgABggCBggEBggGBggIBggKBggMBggOBggACAgCCAgECAgGCAgICAgKCAgMCA gOCAgACggCCggECggGCggICggKCggMCggOCggADAgCDAgEDAgGDAgIDAgKDAgMDAgODAgADggCDg gEDggGDggIDggKDggMDggODggAAAwCAAwEAAwGAAwIAAwKAAwMAAwOAAwAAgwCAgwEAgwGAgwIAg wKAgwMAgwOAgwABAwCBAwEBAwGBAwIBAwKBAwMBAwOBAwABgwCBgwEBgwGBgwIBgwKBgwMBgwOBg wACAwCCAwECAwGCAwICAwKCAwMCAwOCAwACgwCCgwECgwGCgwICgwKCgwMCgwOCgwADAwCDAwEDA wGDAwIDAwKDAwP/78KCgpICAgP8AAAD/AP//AAAA//8A/wD//////yH5BAEAAP8ALAAAAAAFAAoA QAgVAP8JFAipoMGDCBEOJJiwIaSF/wICADs= ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcents/x2709.gif R0lGODlhDQAJAIABAAAAAP///yH5BAEAAAEALAAAAAANAAkAAAIYhI8Zy3wBmoMRymrmqnTbiIHa l0lOgh4FADs= ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2536715&blobname=ijmsv05p0273g01.gif R0lGODlhZACNAPYAABcAABsAABcXFyIAACsAACUMDCgMDDMAADsAAD0MDCwWFi0YGDEXFzEZGSUl JS8vLzcjIzklJT4oKDQ0ND09PUMAAEsAAEUMDEkMDFQAAFwAAFMMDGMAAGsAAGMMDHMAAHwAAEAo KEooKFMoKFwoKEY0NE07O0RERElJSVNCQlxMTFVVVVxcXGFPT2FQUGlaWmRkZGtra3Nzc3x8fIMA AIwAAJMAAJwAAJcMDKQAAK0AAKMMDLQAALsAAKMoKLYoKMQAAM0AANQAANwAAOQAAOwAAPMAAP0A APsoKIdISLJOTod6eop+fuBNTf1+foSEhI2Cgo2NjZGCgpiPj5WVlZuQkJycnKuCgqKPj6adnaie nqOjo6yjo6urq7KlpbKqqrOzs7y2tru7u9yDg8PDw8nCwsvLy9PPz9TT09nW1tvb2+Dd3eTj4+nn 5+zs7PPz8/7+/gAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACH5 BAAAAAAALAAAAABkAI0AAAf+gHCCg4SFhoeIiYqLjI2JbWZtb3BqZpNwl2Zra3BrbY6goaKjcGZb FDNtVG0wLDMyb2ZwVGowM1ukubq6b29rbm5vbb9uZrJwaWZgZmi7zs+MaF1RUTNig2pqZGJuamhg n4rXVGZk5VTXi2KXo1GwbN1scG1Rw6FmMSgzVLhwaG6zZMBYEcVBFHaHnsBxACPKlhMCZsR4ggIG DIowZDxoFWMFGVKporRawWIFhYorQhUT9EaeJZZvgAnrpWjFFhYw+KFYIZHKE4EyTsTYMgEFCxld 0olyB6ahlS5UqER5AoMXmljl0JjpAkaMGCvQtswY1AWaWUJvmpUi08WKGKj+W8j0O0u3LiGAh8LZ 3cu3r9+/hXoJ7hUsJuHCgxMrxjSYJZs2bdhIlhz58eTJlSlfvpz5McJQYqhYedply2ipp7dsaWuF n7LRpq2o7qIMjGzTk5gE2D0gwIDev4P7Dk68uPHiXnKx7vp0i2jRt22Pbn269eq2W7ZaAVMaLBwp w33z5n389/Dyx7Xksr2Fe2zV059Ojy07KmzV7Uu79w4euHjzwAF4HnrlcbGeaV2UNpt08G2nYIL8 iGbahLLp15ogUvQ2XoAEBmeBEEAgEBwBxxmYlhryOIIGfKUlyBV19enH3VsJ0jfhgqNhKF54HAp3 XA5HHEHDbwTYkIOIxKn+54ZIZTnCRls1ckWGdbfF1+Bq3PHDWoXYTZLhbv8VNyCPA3BgRBEZ/JZB kDYQ4CaJBsJhxRMKOUIGGNvod6dzsM2HXWpvxQcbV1BhyCGYPZqHQAXFIXBAcAgMUQQHxcXZRU6H uCFDV4SUs2dc0mC35WylaUkhdAmOxlY/UJw3JoC/aVCEESAIN+AABDyKnCBUkKFWIWjMWdUgaKgx W1xbOZcqflKK4ZxpVGwJRoPdCaKbmOQNSEOQPXR43Be8+nTIG2IY02lp22whxrQ3jioGGXLZeGOV 8Ok4wAc1VOCqmATwEIQGFSDp7W8m4uRdYBREAQYhwXYRL1f4mQaGe9f+rdtatN3BCO1qgkAxgA1B CkFiosWBTIQFA/+WHBxbYDpuKYQw2Na0t0E5LWv4PVdfVLFJKJuXAfAQpBEIDOcmrMEJESQQQwSR 5sgFClLNXIf8CgfOPd/n4GpUTOzcc/CJhrV9HQfwYRE1mGeBpDYcV4MRQih9BA/oDRcnGRQcfFdF VMQ833TQjcZdxtBC12B8EKtmL64AghykBsVlMIQQCHzAZnnkxRkFGWMdckzMOstGXeDUrXZxalpb meN3rg6XgRGPF6dDkBwQYEGaPuY+gHpwsGGFGqDYFpWLVP69nWr88Pl3qah24WWPYFZgA+RhmjnE o7eGqWEABrbBQi3+wYPNXXWw8Qwffc9BRyPP3Bm6fZiIJkqehgL+F4CSLGwhQ/AVPkUz6qWLSuji o6XTiG1xPNoQ/eCHqPHAbwBxUsPCQHEnrvCDXjCqEuDk1afC9QM82Vog0vxDHAWSiEdxGgUaVtQz dIDhgrOZj4SgIkAaGq9vrFvghrIXIO0N4ABCMMKQknQg5OEHXvaJoQbxUx8Y+YwfhtoX/eoGq+Fo IEhDgBoEi1gj1Xhtg+pqj4Qm9r8G6eyDO9qeecKTRhFqiAA6GMIQB5ACE5QhF+t64bowVqPSgUEa geJKliqkvNFNolVsTNkO68aABoCLFHK5zwwjhrHr5OyCyfPfxaL+EkX7CchH2pNiG32TQlGkQSvG MAYqVcnKFTLjlVqJpSwrkUpBlIEJUoCCFHaZS1768pfADCYvcWk1Z3wGMMhUkSAnBi/33GxiXNlK ulw0rT+uyGtemSAWRkCCbpJgBCIQwQ+Q4IMQhEAC50SnOddpTnS6853vDEMupkQxrm1SgLe5pHw0 WbP29IMJbjrAARDwpiEcYQgaAsBuFOpAMAFAoQ8NAEMfWspQkAEdsYGSAKPikJ2hxiH4bI8pamYF oN1qABnQQQbAxNKWtpShEpVoRCtKQX68sEZROE0UOFo42bBrn125aHUmyISHRvSlC02qS10KU5bS VEXbYQ/z+EH+jZ0iD2w2g0qLaDibjkW0qUt1KFiTClGZyjSFx1SEMkoluo0K0Is5zc91ouUsLbWI Y985almbOtGXljWsCzWQGqLgikyRgQVKgcOeJHmd+6zma9Eyg7MUJDrRvWVd1jLqRDfr0N+M9a8x jSlF4eAGGFy0ahMww/6IlVG6ekViLRLNTvlxp665x0VY0kY6oPBVvb40UkaoQWiZGtbuHQWHgdmG 1UY6mgTRSHDO6QoNM6kubyRIslzJI6v2alayAsByRyDC+75K1tACwEBusIIZOheYEyjsXFBqjn0M iKdqGvAp79JPeyr4Fq/+lbsQPUAQiMABpQJWqaWkGlr8wbD+8tUIn+lbFmvskw1L4ik2E1yCZodL XoV6drgg5qxCTdSyCSLic/7gx1ekslErzDZnfRRgXe9TKsXBoai9PSpLIdrX/zr0pd2jQAzYe5cT sCAKDGOx2GYrH54ZTnnz3SR7fOrfHYuWu0j9cYh3E6c2FJMQHylEaGZ7wdakSpIX/J+EIBstK5hj C4fUrG+XClrRlvehA2DUUxsxpfTJdl6lWbFofkrAGibFxlfgQQ56o2M6gxipMB0AEOa2Z0b0WWKn O43D0jWx5rpHbF8J43wF4YQgrXSpa/Srgc3rG4MCYWWjMEVcpbPRCe0RQvlMVY3zaRpBjMEIWXy0 f5Ta4xz+s7QCNECAgkGhndPNMDW7HjQNHRZqGblZLVA4AAE6bOUfI0ADBHAoHP8FU81WehFmkG9O n2MxdoeGPVzLKXZl4yxlTZC3vbWzTCNNhCPcgKXbOoLI1mjUcyuCDEyuDp82arHHQnM0e0wzR3GI b6PqOwAaqEHRGNoDIU6UA0HSQQkhavBEXDSJw4t3qWr8wsE91qbdiRCS4VBxzkq0Atzq7AFYbQFK dfu8uUi3k1XsFcGtC0Lc+WJ9oqCgGl4or3LedwAOQAQhstqsPNY3yYP+rLeoJps4+gq9IdtcrvKp XnB4QtTlDAAC6MvOeMZyuSNgAhOU/MT4OQfRpZLdswv+us1tQZXpOHlji7Od7Vf+caMBgCsDLEAB jxxFS9DABjWsgQ1pSIMbKo+iNqAoDWvIRhqyYXnOk34TnE8RGrjAhS2w/vWw9wLsZ0/72XtB9qzn RDJ3z3tBpLufyiLV4JrcHq8laFrDE95TDFWA8BSgAL1pPvSbPwDqBwD617d+8wMgAPM0/+6HqOtG FRQoLDHnfOpKyrvqzaD20Tzfqr561gE70/VA2HR4itKd1hdoB2W3gvjhfrx1YAQ4VloWWOvhbPGF M2SQFgkSSUlnG8TjT0nBFpm1agS4GxZwA6eWgZEnCp92I8jTXOpifBNyfDQyL262FV5FVrbiUvRj UEb+sHMFCH6GkH8iNT7KElVdUCylAzH5dSWoMkEgBCaSUwRD0kDDFgAgIzIZCHSQFGjQNFcdRAZu UEGDMjER8lg7GGZSEGlycwTd8j7vM3UDYIBaZoOFcCcGZDpfgyDIkifvkXT+9CwLYi2iNQBBECRB wig7ElZouFkfGAorhyAzExqX9UVdITE/1Ue/M2YZ1lQVwANCQAQ3oEYtlQE58AFJVYYtBS6eFwUp cghkMIpwwB7SVUHmsIV4si5oEGrmEC+5NiFQVHgZ2FK/sYdHwChwNAQF1lC7AS5bgAJgQGSEsAIy kBKDQDET4yzN8R5JUQ71BiXdcYLHwg+H9Gi7QQD+NdAmS3UDB7VzV3RQnshlguAriUUIc4JcirUu jyUfQaUl76INi3hbP/Us9aEuZRNWQHIEbcNSwEFQvXEABvWPS2UiXeAG6TgIK0AFwyIIlUA8W+UV chFU1eR1LSJZ16GDX4eHYQUyRoAyawQ9AUAARQOIwngTM2cIVJA/DOOM0XIzk3V8E1ltFWM+1JIO umGAeRZut5hnnshQ6GUJYYYIeiMNzwIv0kAxzQNNSYFbUNEnpGEFWeCR2nhgxOEmeyhy5ZgcaIAT TWIITzADK3mK/sNMR+dPouNPw9cV9YZpNtNrN4aBLpUBH5ABBOUmi5IBGtABsBNsnvhIJnYI6qX+ F1dTQMdyM/hlBpl0V8zAGsbwHvhhlQeGAFh0lxWQARzwATRQAzWQAzxQO+WohqBDGtRGI+NjDi0S SF1hCjhjdLDRggfIUgRpBEDQARZQAT3XASDgmTTQARVwQi5Fmss4aG7mIG1FV1yBBnLxgGzhiD7F iBdYZy1lO47yJgN1OxqQARaAPUs1iMGzU7ChXeh3WT0oWVtRb5N1do+1Dnm1Gxnwdgf2VyOCLTtG nIIwXdaBa93xIJs2IyeYLizSInEWANtSBDQIkMB4i5+IRzbiZoHiaQ73IOOzglNSfPWhkw9VAwfl kw11KAwaWvhZCkl0M1OyVfjXIl1BM8ugDRP+Ei/6aIsBUAEJioHl6GgxVUeDaVExUnQSmB9mZlPb YDE0sn7HNx27xWPUSVz0t2MAIAERAGuisAlqkHmS4HnDUKWiV3q/kA1scHmjtwmj96WgVyyCcAZa kKZquqZs2qZu6qZckAVaADy9V6eAcTMKYmtY00WURI3c4SkTKggv8HyEWqgFYACImgAXYADPh6ge gAMbwKiHeqgJsAM7gAGT+nxpgEdJ0QbrKQbB8laHo5YOw0wR6CJiIE9woAKHh6MKVQF/WaNBwy3v Q6ejsA1ksAbuWCxqcDo2SVt6QiM1Yht/VIqC0AIWoAFXl2WvGiQImkYG1aE7sqmk0JqmgCf+8OKM osNWW5AMhGIzbzEl9xFmShAkNbCk2hZRwFEDt+lSIBAkNNBStioK5YJdarkM1MgstCEXZqCQ0RVG 8AFNgtAEObdUIGAERFCjjIeJYIIAInIAPAAEFhAAujcKU+aWySOBxrCtXicXbPiUT4mR/ZAEQ2AE HRBWuviLWNlSQjM3A1CxifAGEoQXgqCtxqcftLEGF+owEbkNi0ht1yEq/aACuAJYZuKEIYQo3blj /cgDFMsIYlAURXk1L1RApMEcOLOitdFpD4clymWBcNACaAgmwjlWvQEkQ3CSEgWxPLBz1KoILQED CBFJYnOCWyU6+xEfg/OW5cIWozEJLmD+cfMJWAPQb0dQK1n2tokABg5AAYlVkYIjrhklglsyH+U3 WfUkCIFLl0yqQ0ASkg3EUptaCTHwZZiwBStAs6VQG8X3WDazZk8ZMX2nfscnsKs6tlmmoL6RATRY jpzQBRRgBnVSCFQgEOy4Voc2KIU0ns7ijO/YID9rBinSAlj3k4B4YMDzBrRgum6gGvO6f12UT5bF nFwhQX2SKls4G+VyCWI7n0SSK1DjQDcKJptqGkeGCDI7tfsnHS6iX4T0dc7iNVi4lv8QDLqXAvNn NjlAAwGDAHzZAR3AATS6hDD4Pp9whQp5CGAQA0jBMHgiDVtjOmKgDQ82M1NoJdcRC87+orkgRgCG qwMQDAJGkgM2cJcnpEO7wQFDILH0Gw0WgWLfoLxRtgw+uxo+KodnFmgrol6CoAIuhQCwcwRBUAOd CZo5kAMgoAG6slQHUARLoyEwew/3NZW9opHSVS6EUiVndhvrMsKaS1678QE9sIkZ8MAfAAIfADA3 rKAHEMVE4JOKew89FZ3boQZf8ZTN5aIXc0nXkS7H+lnaM1AOK5xhNQCzcwTnKlHzalHIZyVgkA0P gpGgRzMQRjOrES9NnMBjO78AuZ3bE8igEGoOp2LC0CJawV9iB2Gx255qgcBXuVB9pcAqW4BPSwrq 6TU8Uw5GjK1oPGGiGkZImg6sKrj+5UZsjKc0RiCfMMgbCrXJoKAVNgUqPkWNZ2k61oFPgOMVpiDN G0aXkRatE/uHADkACqAAAeDNjmCzCamrXOIV8dVEo4OTqsEML5TKi2fNZqUBPRCvYNVUA1B3AADL juAGkVGmX+oGxfIYajAMlGd5a7BCIB3SroQGv3BKggAGVZDSKr3SLN3SLu3SWJAFVZBWdlrTZpGC qCpdpbp+vmIO6ekpPptN0oUnglAFj6cAC/B4Sb3UTL3UDPDUUN3UUp3UkIdH9hEtmcQz6yJZ5eLP qvGcoeE/zekWGnp4h1efqbZvG2ZuykFjbDVfccEGbNhY5jM82SAXNpVZZq2uuYL+ABbw1wGzxVKn pEYFno7QclkSNl1DH3/EGjGXPNH1DytyfHptVHkmMCaZrB3AmSAQwROseIZXcPPkM9TxFujwlg5j CuYsrIE31PgaZ5oFAkUQBBLssJopw1dMw1kskGJl1iMaGpD9iKFxLG1cCTAKL+rSvFwIJf4VUY5T A7l5Ox1AAzeQAzqgAzaw26m211A4ClH5LrIBCafDIihCBmlQV0BKDs95J+7R3A91ADaQLwK1KBrA md1YA53NAd4Z2lfW3THbEGF5NaNRDrLRgCfXJ6/1nNAyHYvoRTezXVEHkLmSmRrAARoAMNoGaYdX cmjQCsOrWFGJDpJALlJ5WYX+PJNebRvwsg2kAdtypgE2UAHqiiu5om1Q02FZJ9pyAgPLhgkrMDGd IlnoAAy+xywQp85ucIhvsLNdc3yvGGY1996w0y3dVkWzyXZxAgNW8JAMIxZcHih/1BJ+K3ynLIFQ 4hXADR1RMaRhtpNf1cWYDNraiONYLghoYA3jIhaDeXIjnOTVMZFhY0BJ8T/N9S5r4DCVvW9+3V2+ xVdqveGCwBPKCCwnMJadMiGSlUFfUzzCE1IE1AWQYQrHEOWCm+EiVr0iZtlQ2EyIsH+EYMjE82RJ NCFg8AY0AzEQo+a31SRq184KRQMIK+M46qS+3QjGDWYz+YPTFZUkyIhmAOv+Dyc+k9DrOVa4QYK4 OleGPsbWi1ALVkBkwoMldthpTiQh2dQrbVBNy1S1M0fqETU7RaDNAFAB/XaJTop13L4IM8ACKFa1 gwcf5qBJ5bIdz24xGbPmpEdD7m1xvdGdhB1wM6hlez2iE+ZiiAMvbZAG4SwZsdAsm14uhswzC894 PUAEykrNAQByHcpo3lXn1fppopoUlid0A54NSVd0XhEtzHkxTYJjR2UBQbJoYZVxjJJQhvfoFN9k ZQYxeVJDrxUXv2MsFoTcopEF98Z2A+AvFtBjw7U9nyVnv/1iCHLObiVIhOJFL2IfDhOVPR/aa93o Bvb2EBUBJWACUgoaSTSgM7KxbviE08xi2gLklKLh3v2tV4inpGrdAQgAAEi9ACN66yP1clwzX143 3hujaxVy9a366GtH5xKlxZpVlaTQHX+URNMReNSRLh5laFyYPCN/9ITt9nIP9vYHYRWi1W+1LPNB axnUHJNQBfUc/Ecd/ArAAMRfz8Zf/MSf/MQ//AEeCmtwSijiDdOfDb9QebxKeZ6XDQARetQ/eh0d xsgUCAA7 ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2536715&blobname=ijmsv05p0273g02.gif R0lGODlhZACJAPcAAAwMDB0HBxsIBxsHCBMKChoICBUVFRsUFBwcHCQFBSwCAiEKCi0JCTIAADsB ATIMDDoNDSEVFSsSEiIdHSkaGjARETEaGiMjIzMzMzo6OkQCAksCAkkMDFMBAVwBAUcSEmMBAWwB AWoLC3IBAXwBAUREREhHR0tLS1FFRlBMTVRUVFtWV1xcXGdTU2pVVWNjY25ubnJvb3R0dHx8fIQB AYwCApQBAZsBAZQODqUAAKsBAasLC7QAALsAAMQAAMsAANQAANwAAOMAAO4AAPQAAP0AAPsNDYls bJd/f5h/f6hra9NpaYWFhYyCgoyMjZKAgI+PkJWVlZeXmJiXmJubnKaUlKiUlKWcnKyamrCZmbqZ mZ+foKOjpK2mpqenqKunqKurrLKmprSrq7usrK+vsLOzs7yysre3uLu7u8WUlNKZmf6UlPeZmdGp qcCxsdGxseusrPKpqf6srL+/wMPDw83ExMfHyMzMzM/P0NPT09fX2Nvb2+Le3uPj4+zr7PX19fj3 9/7+/gAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACH5BAAAAAAALAAAAABkAIkA AAj+AAMJHEhw4J+CCBMqXMiwocOHBdFwYYIm0BY6XMB4yRMoj58yffRMgUiypMmTAu/0YQJmDxo0 UcgwwUMHkB8qTmaccOgnkJ+eKE3S2ZOwD8o+fvLsOQPUp0dAgf7YPNhQBhcWXKJIjGLHyR0mepjY YcJUT9BAd8rYmeLEiQwqUabIkMGx5JkZGV68wCOwD9ETMqbMYAKj6UImK3LOoHJGBhMVbaMQbruC Kso9TsAQljxlBRW8dEzegWKnTxmie4wGKqOxDBoqhhWm7tPHzp4/d/zQ0f2Hjus9TM4K/EO8OPGo sVHiSZqnD6A+ufsoFU69uklAdgSiOUNlChi23+/+WB9PXmHT3MR/+vnjh2j59/BJ9uHDZ48f2nzw 56/P5z5tpP79R9t96yE1oE920JGgHXXUQUeDEEbIYIQUVghhciSVsUUUGoHhIRVSSBEFFSRq5MWI U9jxGhVgdMeFF17oUUYZLHpBRUVlAKAjAAT0SEAACgSpQAJBAqlAA0gKeSSSSSaZQAJjnHXGFFxM MUcZXnCxRYhSTEFFRl5IQSKJcU0RxRYeckGFHS2yViWOBey4IwEFPKlkA0HiyaSeSzKZZ5BdnEXG iGSQoSYVW3ixhYs0fskFFyLaOMUUW7z4YppucoGjnHECQGSdf96ppwN49llqngmEcRYaNqKpERf+ ZKCRqBRVUlEGGR6CQWOLlEZxKJUaDSpFRWDMSQAABRAQZAFKDqmkAz4QQcOe1AYJ5Vl44JFlolu4 Rkd3VI6JJmtueuilo5VmBIaa2RV7rI7KMuvskUoSqUAHRRTxA5M8ANFBtWacdQceiVrKxRxgiBmF jV5Q2h0YZyZ6RsMZ1fooTFyIJwadBXQaAAH25nkqvQ3oEAQISGqQ7w3UNhBlFDC8oBpEYKBBxx2s gmGHHWec+WiVwH4pppdgkDHpFF0+WvN3oZHBY8fHJltAAESW2sAIHtS75JE3+PAvny4L9AILlj3k mh1Y2jowd1NkOamaYNDRIhWKerEupbmSiEb+i8Qy28CTHT8ZQJ1/F6BDvh6Uam+TLQfpRlQxY9jz HWUHsjPCZGSZoJZKLwqjFzu/5qUU6XYLI6QZTUFsj0/SyXGdRC5AQA75otykqdUGGfAfTmSX0Axl lBCbS16UcYdGcr+I6IdVljHHlZCGaHd31JdB5aKr0/DDDQnQiWwCDYAKPg0heFCDBmC3nOSRu88w w8wE2WdWQb5J4dqlJqrpBa6XFv8t0hmhnpeiEJcR1SwQYOBAvoowgo4F4IFaS4ADiKAvB2yAVOpb nwKiBIYTvABDTGCBDCpXhi5RyUZqotW67JcmFi0Kad1pmJlINCkSbWELOHLAEBDnrA6EQEj+IdMA BYewwx40bkgLyJOqAsECFsCPIO1BCMS20DYthYhEhzqDubr1nRmmKy5zq5iXyrAaAniAByToHgHw VQQgOKBZDuCBD2iwQAzOa0gJ6JgCAvUHFjgBQwLJAwm9tCUQhQhFtDJUdwhoJhhCClFkkoLd1MQF Mp7hae8iAAgW+MPF+aAIPmgADYLAMiD6rUfw8oJAWKCCygnECS+AAQnhgkUrUqmGL+wQDM9Vyy+h 6Ia2CsQlWccjOtEOCBqgmr2E0EYnPYlIz8wjvACgSj/MwAnuKch9EvIdEWlJi2VC1IliyJq2nQhp ZYoCa+AyojKcoSJi+FiyeFRMBkgtjz/+2sANkkkA2SHrRz6i547IiEAqmIRGIbohHYy2SBclLSvd WZQAQ5SruHwpbmUU6DR9hE95yslYmfwoNQMBgzuwAJAKwZJ3NHTD70SUil6S1NEmdaa2XfSFlPLC pkIq0qglK6DHehc9ffTT7qlyBlH4YEl0RgcYSZQKZPjSmFDoJYdRES7e2dKhxqS61eyoU8aqE7MA B9SPgSwBHbDBBkCmAKrtUSClMYmuZPXUGIGBilqCka/GVCOsZiUKIkLUuZqmo6nN6Xt/GhxQiRoA HeqLT0QSw1l4pSVXbeF4ZcrSl/bnKDKwJmHn6lJNqUQseGWyY2O11jPjxFoHEsABzAz+5ZAsQIEA BCwoMypDRspZs0cdTUuha1HxXENAWNmophE7QyCcFqegUg2gzAoAAAbXPXkmS7ESFIED8liAE5zg AJLFrRe4U7y3oYEM3OIQGM5QKEUuqlKUUuRdzUTAijhtoxxLgJEC5yMffUy1ilUWAQ5wLDKcRbfg AhokEVWl1N2wUq2SaBfthl5GbspYPBJc6x5o1qlRF0jPJGoCdqTKoOxhD3nQg1L0wOI8pDjFeshW jGUc4zzgocbZcjGKs4UHo/TBbnbTSBeGHIYuADkMQe6Ch4ys5DCEwUNFbrKHvJDN8UAlEFcGBFS0 nOWBXBnLYN4yQbhM5jKb+cyAIA7+mr+MkobFaFdp2hClaBqxLM0hSwT0wh16VjQwQAEKXngeAovJ sQAsIAFJPJKdNIjH2EGNalLrmHJxC4WFRRUKi4oJeqt4Pz3PJw/ozYod0OtZmk4BCsr9QlALsIAF iK9ZomqrahGNyoAGgKBt/o5GqACFv67rYVOIFRQKlSC7mfMOdPDOXTF9V+WC4VgCoNoDQ6bo2/Hp jm2dmgMHh+uTNLVDtIyCE6BgJrvdYQ5bGPekZAVVLpxhYr7CtKbOKx4wKCBqPXpgEhmnpA2QQAN4 VJIedzS4SaPkDLp1KVsKiGkv4GHPJ9qC0fZwB5zZYZLdYS8drhTXYnVMR9BsFrX+OkBBIbxxZNbK dpy6LdeHrUiiQHtRO3kG4Up9a11/bpsivZOdjfXoum3VgA2yhqQb6AB9I1jgBvRkNT/5iIx+4EMZ 2OwQ3WZJVzg7k68oJXEqbHxKwIwCptnSFicc7EVmcvbUBHDvHimAB0UIAqmSXgQjaiC2/G4Wd28d CCewgEMJQQMMYPBELWZkC3O4ON0IaHPu+EziECM3rytNpS94CEtaCcTGpqYAPSrgBnF/YwjyFcoG WDB38wp5Ah7nBxjYYX4F8ToY6jKQO2ROt4Wa5KjJkPgEkQHQLyrU0oy2IUMVDHua/29bF+cBC/LA BjfgwdeY1IGlL05IYuWRcp3+QAUWlLggd9DSExsGhSnPQSJTeOcc6KDF8xfXVqSeQ5UqXekEXwSB dBoSqJT0ySIkjnEjQAREkDj1ol9QQwBkxAcs5jsFkQcywBQFYU5cNCNwASM9tgewwmsEVH44tFBc QHkQdmpewhfPJlayJiQNAHdEsHR+koIro0HKlG0IKBCAcGILgQdVFgiH1zBoggY29QUqkijl5QVQ cCMIh25QwAT0dUNn0hZkRAY/p39GsiQjMH2nknQDiCchRyfdEz4GRgUwIAOhgRB/sAd6EBt45QQE FDc2BV9VckOvQW6LoiZbwAR/JodzEH7jtjput3928id+Qi8aAHD0EnAf80/+ZHQHKiAz3AQYOcgW vtROXUIiX/CGkwIjdLY/d/NnTmAle2AHcWFf74JaBfA3KJgnzcd0ItM41VUABuYQTyQQOAEs3Icl 5dVId0g0fwVVhhIXd4gGe1AGYhcaz9Zf+3eKDdADbXRyGRSI2sZyJcEFasgaxVVJwohpndgWk1I0 D4ZscPGB4tZITjhoPxI4p6gkP1AEK9iMe/InBXBbKFFuX+Il6Jdbe3ND5BYXlfROx1MpX3KHUFB2 qwMAnTddIKY1QhcCTNeM1qJMBncSdLM3X4IGegAxYHAlvMctwUciFJcWWqJzYncuUECMP9danAdE hShyBVgnyvQj8HgSM2L+M8OFBmooN1R0PxlxbrYSdTMCKxLxe1GgRQFJRsVYjsoCJMd4beeoaAf4 I2oEjSRhk2s4BwTkTnNwakXzkYqij3dVJexlJuQ2f05ARj7HknokOEfSA0GwAchYLfpFXbIjO6+I EsI4j1dVXGInh1uQhFT0Z4mySPRHQAW0lwZWLMXUPZwHTR6QL9PCjlr4TCaQAitAAHN5EndmIxdl N4w3XFeSl2JXPHZQJWfil2oodrzmbP30c8rSeSCDJD3gA4QYKn0ig8lyABRwAAXwkHK1IRVXIhBD I/CFc2bnMxdJI+62IVQkbkwQF872Ua6TX/qVR42WRzGIRxzjdjwClRD+oQc7c2J3oAefuDN4YAfI lh93QJ4hcZ4VlwcVR556UHF0oCBD0RFMUJ9NgAT2eZ9P0ARMoJ9PgARNEKD3KaABip8BWp8ImoPx saAMGhQqIhG1RIec05PP807vVChokAeJ9wVn0FResFCjJh5kMAETgAAIUKInigAXoKIpaqIk6qIs aqIx6qIoWhHi1UXlNmX4kznrZTTzNiPsF2h7VjRkQAd5cAZzMGgitaRM2qQipZslwSoUyGC2+AUS Y6X7kzlksDNImjPt5W5gMDBz0JxOWqZmOlBncXH7424OIyZzkyWoUygXaoZ4wCoTsyju5FmuoaRn 2qdMqp1m8yVbwF7+UxZk21IpV6RVhlozGoJFuoI8y+WnkgovDrAAAACoDtEitAIjaIAwGYErEAYr j3R5tXRDYnJDSlOkCMQAWTOpO8IANUAD8yQnNRB6mNoQ6wIrn8UaIfIorUIG7OWmz5MudwWs67IF LOZZ2dEGFEQED+CqAJCORXADs8oj0hoCL3lQlcR7r2FFgWaniqJFlaIrZ1Ap5wUjc1AorKEoZRAa cbBAIuCqBAAEKyNUOiIC27MAt8oQk0SkLfKpiiIFhfJeaIAlM5Iwg5oR7JWuX6KsgTAGPUAEPyBd Z2qvsCoC9vqkZ8EwlHRXTiUif0lRHUJJIEI3N7I3rhFj7zRoYPX+VTSgAx0gJx2ARq5KUH8QiwLh BzKCEA0TFxT1KFxyJlFFIrTSoVFVMFDFGnQgI1qUOUlqmCI1ekUgBAzgI/RaBA4wqWTkFsCTEFGg AjBAewJxIgREK+nCJSJCOpxDN2BgGluqLueFBg+XKw/Hpx/FARTEAw3QWMqoLxTrp2QEHGUgtgOx BxlQGQUhjIAlsK8xrjQEZJ8qJljCe6E5sDiUMwjXLk26ABxwJAXARkXAATWbs9DhtVwwA4TrUlnC XqGaUDDiKGHSq3YAPQh3K3RwXo5SWk26muATLT0ArWQkGEzwfQSxEn9UEMjjWRpheLWEQlKwQqaq PLf3cMbVJTf+Y7dL+iP6doiuqlw7s6cKMR0E0SYeQp4IZxq8+ChfMrsMhkK38iI6mTfgib3QeqZk RAfuQ7gCUQaxlIPfAVj7+CJyI1woRAVjSjfjhSu4xxqz63ChqSn0W79lCnVRcBsJ8QdJKkU1hF4t oitKkyWata0TgytFI7fsdzOxcgecGsES3KT7uhAQgzdq4lkptDzoBUmxoiWb1V7slyDtejyaC60O gLF9+sIK0TAaMSnjQkuO0kKSVDxkcKq34jz2WDRnEMSTygA79AMFYABmasTcpDP/20L78zwwwj+I OiOoKjeahSgX4SHEWKbe81EOkC9DYKlfPFk1YlFAZii6Yrb+6Fo3OSO5PJgRnbooT+ukAaCWG+Cc 5qMBGiVSJVACBgDGPIsiFeMbzSFORYMoWCJ/rAsjt5sHEqFTuEKPLKwjD5AvNdCkbZWxO3IBFwAA UEoS57Z+A6MSr3duCoKD4bme5JkgOHgfA+PL4/l6aCEDgxeGy7zMSrAER8DMyqzMYRgDMcDM2EzN g6e/DdrN3swQNFywcOoahKor24IGaBOTJNwaLzK7roFsoVEGBmAACPABRmAEOBABBnAACHAAEVAB DwABAv0AEnAA/MzP80zPCp3QCGAAtbydauIb1FM8NRMmj+I5HeIapVxZuFK0NXN+fKoAQQBKILB3 uIMkQtX+sn96FnsQJhSdUHe1JaSjxmIixWmjKFwkLKCzslDLI0JEBA6wXc2o0hOcpjKCJq4S06Rz Q3nojyTixzqcLuL6vNuRyHJCADVwAz5yaODTjpP60A8ht3eGJY8a065isBrCqMInJuoLTCWiqj3t pHQiT7Bc1EGROR96sOw6wrhydTGpZ3iQJlniThqBJjdzkansnPQ0YodV13JiyYl7kXMwnlfiPBsX LOvCe7eyfnwQ2LpKwohiMwgTx5KasRqgAzTg2DoC1g7xPL4xu8+jITOyLXOlBx0a25eZB3YghFcX ptlCv1jNAx5w1QSpAzXwlotcO4kGy/uaVFxQOWcwnub+V9g3hNM69RJlgAfvVjewkgfuxAdR5U62 R9pyQndCEFT0tAHNxCSHk4VJEsn76gR9oAKx0akIoxGxvV5XhyZn8J4Ik8BL7ZMxZo8aYtVyokBF wAOoRGgcwABth2ggwJb2wtiP7RASsQVUlyAYATesIaWDatntEX+sIYQSN7CFcmdcgMVy8gAcIFQL wAM64ACvFQIMYFqHtaT7iiUMOBDxOQcxZM7boraZo6EhAqy37Dzndisl3uEGrtg7sphFQAIgQEFA 0AA27qRkJBEwAHsEkW4yQHXulDaVouTBctGzsl5IisJbMLujdisgXCn1dqYBAH0LAHqIY1aqvdqr sQL+zpMQTKAXlZMzNfxOcnt1hmJFNOE8q4tuEoek8oeqKZ7YxA0ADjDSPNBckYzjgaAHM0BxF4xA lbMH3cR4m/3oYd4qbB5ogdbAhtK0VFQ8dYC9C+6cVQsAC9AAs57pH0VGpLECxDsQdgADUYAQpmEz JQ6sxoehhaIlusJ7vkHDlXUw9w2k5PgugyNSC0CvNyA7ybIBjP1zTk7LyHGzv5NUlbMurwcGeDCm LGV4aELCM3IGCruuOA2sMqLRKo7eH6XezdR5U+OULOnY+/oRXC4Q38EFt3uRAysF7/ZUg/rmYGrd urJ+D38jycekQkUAL+sBQRVQrKXakE0Q8rc/5Tr+XiieNrUSZHqTrod6MHZTSIateffmpx+XvQ4g uiIV8jy+N+UcKwuLEeZEqmpjI+3qsXf6xNMR1y2MtwyU6zovEEaD5i+iU7k1XoZdsMDaqeW6XvG5 ce6kRXVD3i2sI3TXA2q0I6zdEDZiImGyqxohpa7BGo5uKJq9cVmvpVgSGm4w82M/XTfwA5C864Ki 5OMCJlO2vmgz9QprXBXaqYOtoXdAFHIQBHjiU2/ZVpNqr7JcyZOlU3aGB6xhKOu0PzxDQ2gS2F+g pyq7XizyPNkBBzsgAhxg0AfAALUv0Laf0Lq/+7yf0CVwAhPw9N88/OOBYuCZHyGRYuvhBzaR/Hj+ 4GI5lmIn5mJ6QB9myGKpEQh7cAVagAXe//3gH/5ZwAZqEP7ffwXhfwXqj7MQQbb0WK5qkq5ySwZ+ cAeeKXabCVMcoigutKdtUAMAAaLBQIIFCTpooKEGQoMGEyiAqCCBm0AVLV7EmNFLFI5TzuDhsmUK lS1eyEzBQ4cjlChk7GyJQoXKFI4dR4acgiaQnCJDSDQEGrRhRIIJxGREmhTMSCpl0IDxMmXknKhR pHKEeYaq1KtXuXCpGqXMziJFQghFWzCiRIgBHhpNGvfiyZBcZkbZAlPqlpAd807hwnXKFiqBp3gB czeKzjcezipIG1ktQYhh5F4Gw5HKFzIiwWz+KUNTJJmaMUuW5gKGzB07aGjW1DkGYoPZkoFCvq3A zGW5GzlyIUMGDBc6Z/JajZLaKkyYyNGQKXMGquDFgcIQxX3QNlrIFC/vmTMFEEbfNKmcKSMyyhk0 qaeAOcMyJpWag8uY3AiYfnUxs2sP7GCIsxpgqKAChYpot8uiUEEGPMjrqKP9tqCDDjLoEImlw3Ci T6qQyliqKTQ2Gqs/3LJrYAQiBtyONsoG8k4uP6gAI6PMNERONPesImmL4ILDULTCvJJODCnOCEQ2 FxvSoEUCgzoqEBle2AOpMl6AQQ+MuIDCizKCi6o5L0Iiyakz9LBjsDNOKsm8kW6i4shAxFj+sqEQ QGAoBB7wHMgBDTboAIQQRgihgycL2s0OGDhC6g87/LCRszWHGxMmL3y06kIqxlTNNTCWEomr0jya E8WCaCjrhoF+KMKHEBwAdFASaLjBBhpGMHQg3Cj6444Z/kBqihIwePAi32pC7DPAuLDKozlkAiuq MzsL6TNmm51irDGE8qEsIc4aoQcbPNCgAw8cG4GGWUkIYYOGjirjBC9mUCoKjayyCy+aDjtJM/hC 9SIqxDbiS7jQtrjDrthMJYgGIobIock++0TIAVjL3UBig8aoCIw8quTNIsNkIqkw/Jqb6at9M93i sy3QuMNCZjctI49Sda0zIY2dNEhB3uz+0NLYN2PyYg4yoMVKJL2u8gKNL8jk4rky7KLxDDuS5Nmg A4Xi+LIyYIChjy2jgMK85zLDViqZ1Nv3DjyoCM5DkQIrw6k5cbbN3cgOjDGuMlQ4QeyLoAo4CpPU wyqwTUXlCo8+1gRLMY6+8BLrrJ3sOuSMnqIjs5V/S4yLOfg4Ol+s7JgjOcO4+JIvL+iw7vKJZw+q b80tKoO+/epbm4ri7tADjTmC5PG1jlgnbc3Ygtpadhhv12jTDkfaaMjU0BCextShRWyk+ngkSScz ggpCVefPHShz6DvGtzTkWi6pL7xE0p0MZk13P9tAxmeYBA8uJ1cDfCAE2lhmfRbxgvSyakKjwqim K3v5FExmQpNLfe81JXJR87J2gyIIwU8dsJjPDngsjqBhD3qYAximVhWc2AUnfkEhcmrCEiQpKS0M 2VrzRtAqhEDABS6wHfTQ1pE85IEOeWCW0qCwRCiEhCUzw1AUnDBFjkyRCVAoEcOCsoEgAGFnQNGY AiRQgSBCD1iBOOMZAwGI8bSxjWtcoxvXCKw3srEifKhCFaywRyvocY95BGQa1rCGNPDRkIdE5B4C AgA7 ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2536715&blobname=ijmsv05p0273g03.gif R0lGODlhZACIAPYAABwAABMTExwcHCMAACsAACULCysICDMAADsAADcNDSYQECwQEDIQEDQYGDsd HSMjIysrKzsgIDU1NT09PUMAAEwAAFQAAFsAAEkQEF0QEFkYGGMAAGwAAHMAAHsAAEMmJkglJUUq KkovL0s1NU05OURERE1NTV1JSVRUVFxcXGNJSWxJSXJJSWRkZGtra3RhYXtiYnpqanNzc319fYMA AIsAAJQAAJsAAJcYGKMAAKsAALMAALsAAKEQEMMAAMoAANMAANsAAOMAAOwAAPQAAP0AAOoYGPEQ EPsQEP4YGIJhYYFwcId6eoh6erBhYdhhYYODg46OjpyMjJSUlJ2Tk5ubm6KNjayNjaKVlaSYmK2f n7Kfn6Ojo66ioqurq7GkpLWrq7murrOzs7u7u8Ofn9KUlPONjcO3t8W9vcTExMrDw8zMzNLDw9jD w9PLy9PT09vb2+Hc3OTk5Ovr6/Pz8////wAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACH5 BAAAAAAALAAAAABkAIgAAAf+gHWCg4SDcIWIiYqLjI2Oj4VjKS5jdTNeVV5cXnVvcpCgoaKjiGlj JVFpU1wpUClcaXN1aXR1Y7WNXHFch6ShcFBetcN0b2+4oHNyy2uygnS0dXMzrgGfjRIuJTMoLjMm MxJTKFGTKTJRzqTpcygyEyUpDyjyvZBi8hIlldJrhF5jxkxBtsgFigkuEqJJMePBDBkzUkic0sKX oDQzqriIMmUKFBdVZKCw90jSlDFQ0tSB80ZQC0pVprhQ52jYszo26Qgb09Kiz0dv7KUokdBFCn4/ kyp91KzOMlzX6FxbSrXqIDm4vMj0wk2GKy5Ww4oFyGVTFTFpNoldyzZRlTH+YuJuwmSWi5gxXjBV KbuJC167AfuWDTjmk4sCAQogVryYseLEiwFAZpzAsWUqFv/izeslrqbOaT/bLbsGzqYxprhkOo36 0wsAsGPLnk1b9oAdRHYMqC3Foia/b/z+7UxWkxjOx9+IKRt3b95MAcW4rk29OgAKRbJb4G2xbGfl ecec1lRl7+i5y5mTby5e03Tr8GMP4FEkx27avX2ptpum8+a8fKn2G4CdzfWZF8otl1wdr8Xn4AAU VJffHAH19MiBeKWxRmB7ZSIaF2ugwRlndnmRRlpmocaggyzOtsEGBMA2hSByRNECJ4jggwIa/5go HlobPqdeZ8elcVyAfMX+JZ55XLTUoGw6EFHDbATwwEOM8VWQHQ0HEJBfHV65kMg4JuAoyF2m3IVG f3zlpeAaeaUp4CbHHbmaJk7OdgARRQQxmw7ZbeBgDdnZcMAAX0JhQhWJiFFCWf+k+dlxA8Ll2XGW 9mXcXx72dciTsfEwRAezeTCED1jGZ4EFWEYxCEgqIRKFJK4OAlB7d2IoF5wH/uahXJ0uCCpsA9w3 m7EtxpYfHS5AAUUiY7SAgj+2AohkXHXC9VaRc5V1lqbmQZdnsvClOlutdEjEKCJTzGNmHSQSeJaR lHqH14bLlWeit/wCplKDuyFLLmw2mKvsqzKsi4gcGhLSHqZ9oXFXgW3+YrocJnB15twUmmjoz2sb AGHfwCzWWkcLJsy4cBRQxEEInXe1V6JnA7bZl5LnHQcHQGh8umd2CJDs4JdTpJxIFC60AJateN21 hoCaNB3eZ0wKd7F3bsb1KQFBFMGDwAMbHJvJXsmQCB1lEYQGc3DA2SlhacgBZ8UKCubc1F64/BoB FNw3QAc2RMiiBTkAQYQN3AkyRhUWOqLxGGuk511cabxh6Wp3UbqaWUc+9yltG2S3A4tcZ9dnbbWO 4cIbKIBCqZttRn5XHBmnhymBy/0oGoIrlppdDqQDUQQRQtCAuiBzxKPyhbhnQilq/mVuYOcEBhje uLIRQEMNByQLo4T+g9BBkOPe+kon5J0/D9hcd68PkBeHtBDbBh6ILfRsX47SoXdt4hUdc5ZSUtZg 17YCwa93HRDd/WoTgBOcYHmjmJT1xIAvEsFCNOojzsz4Mq4Eem2BtVGAAvInCuOcRlOo+cuRxOMX 82CsW345UpN6BwAO1A+E1DFZBAGSu50hBy524ZX/ZPahqR0Jezi0DglDsYYmruENtHgiFFmiIU80 8URBOdETPabFyl1RFmBgghjHKMYmkHGMTWjCDM5oxjWK0Y1kjFVb5khHSCzOMwERjZzMA8TyzKk8 gPTjXFqyhAYYsgE4SIIRNHDIRh5yAY40JCQjecgsZCYm3mKhvo7+NIWY9KcjHVFNTDgyBVJ2chMf MxahiqCbgBUrYAAolnyoYyxEWUQMoHSOGMrDMQDFpEMxKaVqOhKFYnKkmID8l3wI4AMi8OAHOiDA K2NJLFr6LZb3WSIoFodJLnQyl8A8pb5+OUpifjMKHfpYNQFggSgFCpbTdCU1/QZLampTEeMTTycF CcrJ/VIv+lRNMUG5Ci6Q0kQrug8BhGA6IvTtlbKUJzznGc97FiINJZgABDVZUL708kTB7Et/ANmR cmqClFX4Fyx/VgQgPBSi14TNAQSFTfodCpu2dEoaWoAUQsABHks7UzBXoTlA4oWgnVpFMKuA0uVw JKUMoid9itD+AVfC1KrzBMAFsuMDmGLGFg+oQgoSsQZ4PGsQu+QlUXdZ0r0QVBP7VGspSQmXgY5L oRyoAESxSc2syhI2HMiOEKT5ymWloDyJeEMqNgrI0ZC0pARdBSa+WUpzVrat6iSWKzsABB8g4Jp/ jeduCJCDIHjgldK0guKgQI9EpAEKGnVYhzazT8jyki+AROdcbVtZ1ThpmtQkwBCyUwOY4jS0riQs AaSJANVepA4QHMQbJMBUQhznLMEZql762RelWlapw8ylMq1aLOEVYQNX5Ss8YSrN5Q7AuSvJyyLo AMF8uXBxklUr1sxjylNyjLIcy2xfi4WAGqBXtPS8arGWy2D+LylOAjKoCCLSVQI51gGX1ltSc7Tb L92GMrdujVNCEUze4x73qhSwQJe6hIVXpcDCg0gDCh7yj1yeEg5w4KY3RdlYb3Z0qAQti0ojOgDC KvjEwH3lBvjEveVatBBQLAQuzblJTOhlNb/MpTcDgtJSdkglMCBAl9yr4PQWmQZGXrANuHqALsF3 FFMOpVL96N/fcGwT+xTlXN8yVJUoAQEUCLQHDlXmqx6AAwpGwA+CcAEGP7kRWgmygM7CS+fEJFOU 9SYpp1xMMLf502kmAAK6NIAVtznN5C1ye3NKikhD9jl08WZMAIpfUG63IyftdB1gUGQFE+AHzuzA BYbNgQ3+XIAChNVsoR/NiOXUlpxzXupe9FlOHnNElBwZsoItkB0i3KADHdheDTpggc/GU9kQZfYi JvvYfroVqe0GEIB5mYpds7e9BwC2aS+wgXB3IK+EPvJ9IuCALvimpLIe6lwA/OyY7NKg3/ylN4e8 aiMToAIVGDWgKVABCgT83PUcAQnA4JtMSBzIbd3nU8EZaUz+koLaZu+CZY5q49ayAOpWhFampmft amUvK095xPUsZHujduY1r3lENct0AOQcWkQ90XMay6myNDziPY6rP2BggK573esEMEACxP71rheA AAXo+gAMUIC1s90AA0i7AVpcx7rbHREsMYYxmqh3KT7+0Ylv+Dvfg9L3vj9RFmeQghUWz3gpKN7x j4e85CdPecm74ZYJ55e+9hNIcFY6rn4EZEtg8OnSn1rMDU49g1Xt3vaOulhvFkVa/fIhUQ4zkHQm Ke5xP/oDIOD3oy59BWhQAdUbX/UDoMENlhv7UOhlNJzZnFtxX7nH7p6cn/gzoIEf/AoMdwgIMP6Y xTx+43+VFA8XJNRkjfBgogb3vCVpS/4caAoAv80eLMIFTF3633N8VYEGagzWfNt0F4GEWwn3GzwW evEnSFXgD9pnf/d3ABTAUD8AagjwTBdQARbAbx5AAx4gbPZXfgR4D32xez33fPAHSM/RSQPygHWg BG3+xn39V27Cx2SrYkM1cAM2QAMb0HHjdwAl+AhpdX1ZlmXe0nnQ1k1ftmulRwE54HHkR34UcAPE RwM2YAEc2G/bQwMcsIHB92lDiHeFsF2452MomGftNlTm0UlbR34HUAE8EH6lJ2aAUgQ10HEcVwEX wAHFpoUBeHoHcAWPkAYCIABnJQhmCFIL2FhHWGnWp3swGGYMdnqV2GaEQgR5dQE6kAMYp4dhOGZi GD63oAhTUAIkMWUsqIL7YXvW5y1xtR+n9IbH14eVaGy/1zVFQAMT6AEW8EwV8GnNpTjbMFaIMAYm UAJmYytLhSTTpzHWc3JLBXpZACIMolyplwOoknr+bcZQRWAoY4YAQOCNHTCDCECI0oBOiUgIc5AQ YmBdz+ZLPGZA7cFNKwiJ5bF1vVZxy1V+DdYBQyAErNJgNEAExFN8YnaO0kUHOhRjEgABEKSCTAIQ B8gcHqWENqZ1UbWPC9Z6+9hg/oh6KbZi5OdcO6WMinAKNFGE03YxV9aKkAh6kfVYqSRzqNVeOHlo +9d6x9dm6CgHUwAH0UUIdKAwFxZXaLI4CyiL4gRMuoeGMaGPEGVxVyVqBLBm9TFq5Bd8ICmEggAH STOUK1ECKGCULFkekkNOZtFjTKJWjuiGI0ZzDWYBXbMDOZAdc2h6Wpl68CUDckAThlACi2Jdtmf+ e/bljG0ZTtenGuoEUzcABHm4cRx4h0XgAUEQBBwQaL8ngNg4ho3AQo04TLBgj3dTUO0Gi4BUk9iE HS2VmXzoh3eoiR23KqsSjB5JZk+XI5x3hq6YZ7E2WUnYiDD4AjB1AEJABDrQcVtYbDvwAzfgcb4X aB0Xfr02c6wWQaFXkUsZXs5xgsHJe1FVTaWWcZe4majWYGUWAiFAcr4gkYNBIuoXSBbEP6CXjyN2 YhRVZvmpYA0QAQbnC/h1gEC0KbDom7jVlpw0nPQknqnmVzbHXgaQm5GwlC6UF2uAIiHFPjzGMWsz Uvb5GktHZA6KVSRmVRJKCHKQd3lHeMuAYyz+gWPG4KIrGqM0+qJvIAtogAVUgAU8uqM8+qNAGqRC OqQ/2jiioAxzID5S8ZfLwKTKwKRN+qR/uaTLMAdS+pcroQZpoAZc2qVe+qVg2gZcygZs0AZmaqZs 0KVTEUElpSE+lmdRYGeRZWvp55ZwOSzJUiVB0AGzST8gCHC7caJo5X5TJhjth1SYsHJwdW2UpUwD 81msuQMXYAE2ZAM3cAM1wAGfBQDnNwqR002qkT5pEEymBCJigEyaxjHp8Uv+ID/xsXQ1JE01oAPH hgAWwIUewAEqFqgWYTk2NidpgGNyJUwCZUy9pRxyJmDVUU/ydFxttodSyKsA+qYJVx4ZY3X+SKVp x0RKHgZKjrqsHVmdJWqd2VRyMomPrvZUQ7WtlWVM6ARVrkobqBWdWimuSCaiTndLtQVZb6VPxkqq A7WtxtoRyiofRXYAlNoBHvCD4UdmN2lm+eoIaZACkWNd7dZWRjWqA6Vy7TpX7vqu33oAVaVqB3AB HpADPKADBgadq6dcy/YIUICMOtRyALZlP4esHJMWTGWsG8uvwxkbFAAEyoUAG1ADzekDN5BXe8lg G0BoSqdubxAPFjZZWoatHBMY/REX3+WxoDRQUAWie1UsCAs4OmCFDNsBebhiN4CQVOlkMAsFMhBU 8GJZmbAKQUYXAtG1c+quJeUFmRVaOwD+BPv3ml+YcaFTBEMghRQwbqHoe7/nXG9QBSUglmkAke9o K3o7fTb2G6NKTE8FcR9bTLwwHQoFAFryjQe7faNmAXySuP92l0WgAxYgnR04qeiYBg/ABWKCCJcw ATr0SaU6b5LFcOAlsKaUCZ/iN8g2ADewAxYwr6V3ATSgYoB2l6Pif6vCbxeAjnQgA3BxNjjWU6Yw pwiHcD83jR1iTkGXbb1DAMIzBHp1k6BmeqcWh7ZpjnqIjiiBAhJWCHSAS40DF1yrZRm6hB4iEP0l TOUxLqxZBM/LenVYif3IjfU7ioLgD9RSCFEQYXK7S+zaT4WqIaqwmCtHqnJxVzrwA4j+1pH9GJLi B51xeGqe+ZUzMAM04WoExREUmVIuilT8ClmoqhrfarASPH5iewEN25W+N79012ozOadvQRg1K8CW 5bUdMcTzSoMNVgE/gLjFR7LmaHozvAi7BJxMJVcPmIT8ehyeq74lJWCvRIF8CIinNwCrhIcsbI6b 6WYlFxAKB3EYi8Z2e1ltXFBgFjTEQoF9CG5gKIg0EJCswnpwGIYEMMY6d7X45VHki3Km9MHoBBcq 4QRDoFxxiKsbMLsN+7BTeYmoV8kWkRZYF15QPKwfRst28bXShE0UmLCFu5eFJsmpt5692nJ1m2WE rHuUhRa3hlRYLGYpVptL+8ulZnz+GGBJvmAK/kEYmVMn2JJHeSEx2GIMlRMQRuI/LSEFDpTOKqAC K7ACLMAC7bwC6zzP63wCKmDP9JzP8xwGd9fPd3cik2O1c5ZLcqEagZFnASJ6dRADC6AACcAAEB3R DIABGbAADLAAGJ3RBZDRHN3RC9ADSHAEZYB5p0QeBL2zomuoIPKm5MRLXkC6D+ywqiyiodV0d2gG B7dPJq2uXotOatx5JU0esDAdBDCQZOaRAldmysUBHdDEbIprHNVfGuNWPdtP0SEx3oI9xxeuqyau VZlmgqo4wYQzKBdxnfSvEMcclIJZGwkAqccBlehxXl2VGLfKDgagkYZbNvbBlxX+BQIVyE6p1aIY ju/bAS2Lk+11A0HAk0VmydBysQmst+/ayZEdetoGh6IYWNlxgdzIk6g3lV4JCYDJE+wXV99lTI9l vOQ7BQJWh+FoA0EguCuGkF982Ko3xhgFkTVmhIT8rs+Ww/31WCoVS61cv8tlq/5oicfnXvDFBd5r ig+wktJWTlQmieGUwLs5BY4KwZ09wa3s3QiLngP4DBMAW67FEDNACDo71UCGSSgFf9waE2jgNibn qMt9397t3cD8JarTU1dBlu9yR+MbV+qKxmhphraWtXjxtRdwAz/QaKpnasU9hd9diTbEx9IwAS0g Aa5lAufgMH7xpnfmYx4Gqs3+0RlrQGV6UUxOcgN4iZOSTIFc0sIJSeH9yG2VGdp14BdiCQdvsY5/ 4XkmbWPWnTm2RarazSAIoAOyq2rAvAE/UI70a3qtjAA3QKsE0KmNwJAg/lYJmHmNVVI8Ddjl8S8V x9X92LjR6QEwTOXj7QhyYAIo8C5s1bVsWMB6trdr7KYxJ8n2R+N6bKs5AIgYN4Llh46NELXkUGNB d9ZDF+ZwZcwB20l5BFUw0AEwMq8X0AHIdgBJK4yW+QM24AGkXgOm7oU2yGCI3ghWWoYDfBIO50nz IjXrulvf9D5J/gT1g3QH6wEaJ4wU0MXD4wMpPI5B4JyZOX6OjQheMLCUjkvnsAZzvgJg3Nqmc4AG UzB6Sn0AOVA/qDeDHPADQJCyOvBMsb0DNrABUui2+mGsdmE5AmF1oKq3kdWt2u3jUimXMe64e4hx t+qHPwidA7nshWBQA3UikIOGlAVXCKfwBeV5+W6T4ieMai6KORB+BP8yfDtneZFyw7o5OntUAKZS Sod0iD2FJFnhDRbW8PKxoWQpRuSvKKUt/ARkYOZrC0YDP2CbwIx8VOkAIvCfpDCjeveXVuqiQYH0 MYpjKfqiSJ93sqAGWjD1WtAFVE/1ZEAGW7AFU2/1VO/1U/8FU8/1Vt8FXwAGcRAIADs= ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2536715&blobname=ijmsv05p0273g04.gif R0lGODlhZACJAPYAABcAABwAACMAACoAACMKCjMAADwAACcQEC4UFC0YGDMSEjwSEjEcHD0YGC8v LzYhITExMT09PUQAAEsAAEUKClMAAFwAAFAKCkMSEksSEk0YGFoSElIYGGMAAGwAAHMAAHwAAHwK CnAYGHgYGEo0NE45OVE5OVo5OWI5OUJCQkxMTFVDQ1VVVVxcXGVTU2tTU2tbW3FUVHxTU3NbW31e XmNjY2pqanNkZHhmZnxsbHJycn1wcHx8fIIAAI0AAJMAAJsAAKUAAKwAALMAALsAAMQAAMsAANQA ANsAAOQAAO0AAPUAAP0AAIxUVINtbYhtbYd7e5B5efdTU8Jtbetqav5ra4SEhI6Dg46OjpeMjJqN jZSUlJ2RkZubm6KRkaqXl6eYmKSkpK6ioqurq6qxsbOzs7u0tLu7u8G1tcS5ub3AwMTExMrAwMvL y9DGxtPNzc7S0tPT09nT09vb2+Lc3OPj4+jl5ezs7Ofv8Ofw8Onx8vT09PP4+P7+/gAAAAAAACH5 BAAAAAAALAAAAABkAIkAAAf+gH2Cg4SDZYWIiYqLjI2Oj4VnWzaHXWtYYZZ9ZXVhamste5CjpKWm fXF1WGdza2tdZ7BtfXthW10wfKe7vLx1dXFzZXaDdXN1ooJ5o1hzW3G9o2M6wXvHe3VdxqNnPBAt NrN9x30tLWE6PC11kCos4DU2WCxWEJNW8TU1WOy8PH1ndLR41wICCx4pRsXZ0sYOK1TE+qwpc2bN mTH9HFmxUUOdjTksuthrgaVFjRZlWkQrw2ONjTBjMlkJg8UGrzbW2tThY6fNnTvBokWSCE2oUUJ6 xLUpsyUTFkxWxB2dSnXQnUFz9mjdSmtO1a9gw4odC2mPnrNo8eA5qxYt27f+Z/PkcasHz1y0utSQ 2cu3r9+/gAOTgcNrIswxXRJvabp4zJlMi291yRRri2OmNLtsKcPZqwsAAQCAHh0gtGnQpk+nLlCA tGjROXxlKhMmU5eYtsNISpwY8RY1cxJT9G2rC2fgfVyodh0adenRopsH+LFkSYXopQUEiL0rjuYy c2CWQQwzDObJtW+HgQM55uLJTYdD+5y6fmnV959nR8KEiY8B2uXH3SmvwNRGbeYJZ0tkt2mWCWTq aTbGGJZN1oVnr+FHmobOgQbCEkYUkN99A5rSBhZNrVEbbelpxmBvFMLEG29hxDEherPQZ9+IPOaH GgAARpchACWWElxtMa3+Ecd4XaDYlC2QqRELehZSVoZmEqqR3IgACGDAANjdp51z94UJWgU9fLnd OCd1kUhwW2QkiBzmXTmGK7QthiJ54+kW04y8jcEkFljmmGFoPixxxAD5DVBEEhb46CNqAyzBBBFf OiFIGDWMkUgXNegQRiFtkLGUoGWoSGOCY6iRSRqCvjdZTO4xltgafbwwogBGMLGEAfl90J8QPf5Y 2gSWYjoADoJsYYWbiMxRQxlSCRLHGrg9CaF5uMk4HmK8WXblYrl1kSOPICDxQ4ClGWBEERNIyiNo BUwQJHcMRVTIFme0AO0gE4F7yy25fbuFirkt2FSEhEoYxrk8sjvvxBP+R8edFTpg8SZNhBGC8MDv TYgbbVgwqYaFmmEimYtNmoercj3Ky+XMEohIJpF93KFCDf8S0sVBhxDiHXm23XZRtrO2euMWmExJ 6FOJubxlAAMwGvPV+pXWQQfGlsZdFy8lUsuFhQSnHmb8hkFG0VGv+KBlIhM6RsNntIGrrhMYcYQE 7HadddfMNQebIDxogggfbTxEyIHinYfklRAqVjSqFm52oW7UJsdrfyBgTWaZ+NU3eB9jRHDGp1bw EDRWLFbU8mwIcmYLGIQOXAYZMZLbG0zzBQCEogUEKPG8nwfgJaMb4txHVFYkQkc8+gqSzWZzPNaw ZWdQRIeqDq4NX3H+5Lo9xnxdFgCm1kJ4MLx9o0kwxBGKgtkhd3PwIKcjbVCYKrgSTnjGkhNqmMjc UzQs8M8WEHOOAZTAhCSIqGL6IUJ/+hMv0MVmDjpYQ/NGwTj0EMxPE4rDRW7zwRtFLW0ExATE8mMA SxnhfFgLDRCYoIQjAEEA0AnNBXm2QUgcqSkUippxXDUh87RIbYkBg+TeA8Q7TQ10FQABsGQmptAM YAIPTJ7y4HA6UrSBQQyq00Vs0yemOKY3NNqMnda2wg78IFJXK57guCSkHRRGVsWZDG04A64x4E5k kPvThJ6hIsSAoXcBkICllPDArFFxUvZZwQquUJhMCAw92ftTccr+oEQozQo9FIrJlTRjKAAUgIFJ sJocO/QcITGHAAcokhdldKMHnSGTh2kQEh9kHCoZ50+agAEBhnmBEFBgmMhMpjKXycxk2pEs0AyL LqJJzWr2oQ52s5srXGG3OGRzDW1owxzkMAc4hLMNcPAmOMMJB3Bykx1ROMEJUGCCetrTBPI8QQn2 WQIT7NOf/vznPQFazxJogRfC+FYRL5PJCU2EWtj8FmcS50fciIwMXolB1aomgI6KqWqg89sAPJAd 45lUO7IcxRzGIE5BHcYxMbkIeMy5hjkkjjaOsQMA1dAtzhBDowDqqEezUzVWcmkAwNKOUk0aAGY5 YpplY8UtJ4T+OzMIKnvZOycrVgoTPInyDTytjRkeMgOOAqikJZUju5Tq0aGG5ga8SKcwBghIM6QB d7dM1bVEZjdajbNbIczVRt26vl0hj2oAGqzxApRSSMiBokgqIkVuh6oymAFbE7LsVFdEV5gQ5gWJ FepSKTaAHvxATQMogAFW+yWrodQRZeBIGqJqUZGZBzgKxehSUpU9NfCUVkU0wx4zutHUnpWpuwqA D/ozhC+pdgITqAAWg+o1QfDhDMkoRBlOgitCCKM8dK0btl7qP98uqU/AFRQZcEoHwSbWalUEnfGE 0J8jYHG1EpiABFpb0tj0qwv/QES/LlI2i3IGp2uAQ2ZpBZP+M5ihDTYqInnLUxuvgFYAjCrsjiSA BCR8wADmYw1rOHrS2Owhg6sjxJ2eVYg4kNeiEEZv48iQvTrRqk8IOowcBDvaHfUIw6UFQXE56tbY XIIkifjiR1qMpPWOEVUBO4xlKWKRMkSYjzlW745fINSI6QekJRVAAZAg5OJ2mUS04MSoosWRqywu sxWxap2qDEg//u9oosQdZ4ELDS67Vb4BcJcShLBWpKbWfIOV2IBqsYg0dBcrtDoDrMTj4DOsF86C WoNVixgHM6zIDGtD0GfPKsfS/GCCU+xo1UQ84gwHCGcYZMGaC1GHdLh5EPk7jF4WvJcDo6qzauvW ellUG2j+NEEIP4ChvDi8BCIoNXisYS2IzScxnNnBHZ5CRMpSjIqRTRa9ZrgsGcQwQPBSNnYSLnYf pNCfDkByRGcVKlINoN/9tla0o2uEKxBhI0qzaICXpuuN1SDn8ng6x7Ng9xIkoJ9SB4DaSM1vdPUL 4uM+p7GP6PdV01tnyUY63AbGLHBnIQMQSCBwyRuAEJZQBNZIoAJbs0AF9ktdwWHcEQpesEJR9Uf/ CeqqauDjz4VLq3BiiDlhus8EJihdC3zg6R6wwAQqHrwy3bwRcfgjlod+ywaDGlWfaKjsbDsGm3pG UkYVjaOSIAQJWMC0PuhB1KeL4TlenRF0EDhwKZK9MqT+Ieh3SvBSel6etR1nDW/oAwxek8OkN0oC HvBBEIDgAw/MPHjVBoBTCQHVQnS+241Lb175fmNJw8EMUhK4lMdAmM/kcI5/xrABOgACH/gABBbY L9/GdJq7LyLXlznMS789Hs6sLXtr+O3Pi/jbHbseOtgpgBF8ILGqTaADH4h6zWreSuWdgqsbX71j ZNpXiTqaj8afkBq4aIajMz6HFZiiaVSNX0SX6TUPKAEJfK+IlSYtsur1LWcAB4D3LVyUWZxBbqmC LWXQekn3fj8GGhh2ZpOSAAzAAPxnTY+QXX3webTAedC0FXtwByN4B3bwEyiYgiq4giRYgijIB7pA B3L+QE5xIAc1GAdvcIM1OAdxUIM2+AYzOIM+aIM/GISpcBOs0C0ooxhz8yANAxNmgAkSAge0USUY 8UT54VFBJW/vNWRm5oWasgtrEBkocht6hiLFUTSSgSBkEBnckhsPATNVtFTaQW1cOFheiIcDEIYE 8hRQYxyg1iThEhOEAiF5QjA/ZyETcnZMNVqqVgQgoGqSmIdDBmR8aAqXsBhZ0AW4YxxkoEdCJBmI UUTkcgZB94matEJZ2FYCYHuiZVaTCGSTuIdxlR7poUbi4SBBNBvCxRmRkVmVcxuMGGYnJVQWUARB sIVBFVp5iGEZiAh1IFHEhjIE4yAucyfttCBYoET+1FgjubKKxWg8A5AE7SaJE9iFzFg1z9hiwvEn 1/MUK2OLkKMkQdQwijEwhpIdjqiFR+ArBjCBqvaFeXiJHTgKY1iKo2QLT+FHayiKu9M28HELhHIu BkAER/ABJyUmYuYBuxeQQFaJQ0aQXvQUNEZjZKg7TeiGiPg9ihEuYfAyADBDDQRfi7VYonWTA9AB RQAElWiJjjAHNpACsyYIl7AKREcTKiMZC+Mkt6BnsdCJA4MydxMAH2ApQ8BWrFiM8iYAEtADQlAE erhRIokIewAGoVAIY7gnvaQygGIbKEkZFeUbM3IwWyIAFuABGTaHWgmQC7QEH2CHxWUAQ0AFfdD+ Bl3gL29SAywmNMTxGGD0QQZkiy3SBdw4HrUjGbOgKz9GhzcZkAOQKMn4kRy1XFUwDi3wCm/iRxrj XZ3EiU1yC1nwhxSGHgXUJAbUhLr4MlnYiFipjzjZA4jmhcJSmoMwlIMQB/FgnHXgKrcoGViQBU1x NLujNrXBNCljm1BjGcMYX0PVmVtJicHpAVMwDjbQFG9yOWg5NxFZiGXokpEFBgvzHtXph1iCSHrJ md5JiQM5DjDRQ4djnGMIGe3ZnmG0NhWlHuWhBi6GIu05lcgVjqzomRvVWiG2UYj2BDljEV5BljbA AtXSB3AgiExpnYnhJJYwRkxhHIGUIPC4MOf+0lYPipXvJWKHRqOrVlyasgcq8DCJAAfysJqQRhP1 +CS2KTKPcRtl2CoUxqAMeguquFZKNQBPl1932QMg8AFSN23TxmoX+gg8iAgKxokVQpuCaFVrw5Yu QgYHZ5vk4oet90D7aDzCwgRGIAQWiQRHQAQ/0AFTJ21cmlpjCQmvgEZr8InzeQvMWZ332BRlyDRM iSKZCV90uFgd4CvI+D5JkKdA4AHQZW+sxWoDgKG7cCBgMIoyQkJoyC2DVKIkqhj0uSA5MqnCox2O AgRUCgI90AMf0AHSJQGQZwFbSqOB+giD2pJMFEZA1DJNGj5Mai5XopvEyJlmlVr45au+mij+ShB/ XFoAonoKIbogxnpCmCCgDcambYqd8BGrvImVWviRIsZap7YEWPSn3YqJlqSGcGObNJEZTdGG8Gib vAGPKAKtyNVlWymarLZaUUej5iNPX8ALd1AHdjCxdvALxzCxdPALGjsHGfsLdHAMG7uxGXsMV/EG aXCyaYAGJytpKYuyLIuyMBuzMssGbtBeGniz0cQ4k8k2Kso2RXNE5oFLheoVN5AARnu0HDACDXC0 RssATcu0DKAATGuBTqsAGiACDcAAUHBHIPMeDMqJjsk0bhghDUIRnXgZ7MAC7zcAvfID7/e2cNtw h7KOHoMlk+mollCdZKiLcokgwKQZMMn+eAPQj8TCeMsxJMnDI3SLa7zRCk5jnQOjkPLpImILHzOS CYHLeBXgAwyHuEh3HzcKUj+yuERphYR4kgvDMtSoJwwyHmDQVckRt64kOAAgAcomZvRWAZdHk77n gYX5Pa6SMs/5hCVquV3LuhViG5kLt9D3HEGABHxTNfTmdCAQdV8yVKRbmCU0N3ryNBYyrk4xoiN6 rOdiuG/bSqVRlT2QWAZQAR6Aq1hqu0M1rIOwB3KAXaTCqjKiqI0ajysTGSATkU1RSucLgULiq6WR Wi8Xc9uHvY6wBS1gBdlWDK/wIkjCU7wBnUw0l446trWhE7FbwHOkRR/lcsHJVPQrCHb+YAVYwIHX dCCT2yeAh7wBTLkbrCfCGMIJTLvouyGORDWyWJNr0ghnkAI18GjWAiGW4bcJAsCXiyVO7CJOwqOu JwA/cJGnETg+Fq1rpSnG0AxiAwufpyryOUIJorrV2Jziy7rmEsKndClj4sM//GPEuCZqkAJloAOJ sAWFY5xfpMQ8NabyiSDBCJu/RCFiuxjlGwBDsAQ/IDo/7BzDw67G80wXgsRYkTgbimuW4yCUCcXt CZEA/Iu+NcoMEcJdYrvS0SU0ySMF0AGYR6vvS11GZgVI1n+YXCDFEUT3OL4BfJJBd8OnLIepUXdz XFIDIEGL4lEe0B9BIFSxcQcYMcH+hLBdR0wqSzO5vjHKq1I5TcFFx6rIWPgcb6dhwvPGTNABtNoD /bEuHXV3a6APmywIpxJETekeCMqEJ+SLugMo4iyHhZaXuxmlQ8AER/CPHVUAPjAEmBcAKcwI+bOq DikovhSKjymfLuYiLxMgINVjBSvEV9RaXjiB2atgAvoibQMTTszNo5w9Gq05BivEMDqrElpciAZk 2btStSIrSpkeJmrDy3oLqQKr7oWHXSap+2ihNoqHD/17AYslUH2sJoq6v8gUUfmSfQBUXyiOtFoB f8lWFuqnrSaWXDuulwTFiXzRLbqGKDMLMTDWsChUE5AEPhAvUYphqmUA9gaqVdP+1IpgmMVmW7R5 i1A9l4BSJegBDTSAAQvQ2I2tAJAN2QigABiwAZKtAJMN2QuAARnQ2RmAAaD92A0AA2CAs6Y9Fj3R gzwYB+kEYT3Yg+j0BukEB2/g2qwdDMBgdsFQTsSABl7w28Ad3MDNBcTNBb9N3F5g3MK93MbNBjfh h+NavDSBw48qK4TSdW5oCyyVKzcZoxMIjuxKZDfp14lQlE/RIvVYiEqJrq/pzaKYOQDtWjRNVMJD jKjBVsaTvWmZqlmAO45qQGUQ3YNEMGlNopvxP1NTAESQBOtyn3h9ZpPMrgKQvWnAL6+ZGdjJuvsb ROOyxuSy3cohAJU6k52ZaBn+CaU1eY4l4ruLcDKFWogZ3qJP6Ie8BN2PikDc/XBFgMXdrWpTVzU/ QH02mcDLqGrkjQgHWbnYKeNMUxt++OE2fpko4hneqVT/uFgF7cgFsLkiTWI2GVTPRCCUK4Vl+K9P /t8LqZBNqp5PYWEaaZMAqR0SxARIUAEVmteJxopHjpabQSGh7OSPGuWRCcCrgMgDy91Z2ZsdJQFF UASwvIWi2Z338dB1YBLcZpgXIZ8UYVN4i7xnLryLEXRQnJlVDumSLjG8dx+N9M7SswYuLD3mAKBA tBiu8BjhaxmMgYbe48QsRTLW+VklXuUz/aBeVl13UANgoMfRcg7U/Lst2Qr+YuskU30LjqEGEikr 5OG9G52fnZnijbibPBKGk8BtSQxg+QsZ/+sgL/KLKiKR0A25hbjtwm6OVXRWMCfQWTPhtLAFB5EI ld4CzX4gUL0g6G6sq1oZUd7kWRAGsHI3Ve7t4XgfFmApPNnV97YmfKADLJFkz7AF5/5BmAEZPDse 1ZjwT3NnpJ7A313fLJ8firQEQoZhEpStARLmjKAVzV5IgiJOukHtC+OWllm8tfPulrEU8j4BR0DX 4t3duwKsoGspTAAEaNYIe4AFOjDPhQmMG0cctXO5xyq8T86JzwrTjNwfRnBv70WBGpYuZ48ad9cG PBAG/qm9d5Jj2PK/1C7viBhuK18bH+Ghm7jrA6fl0X/mOcPT1BOB5NNpHuyxBZv4r2u4i82JR+mx QgZAjlIfQxSzxfqtlDztxE7BhPwTlTNCHmSjmYlkKUegYZpfGnCaHfot7b7cwWA0mb3htc25nRYg BO7mcDEkmKs+xH1I9NEOMgIb1dR+BvbIMligiocSUuwjL8clPLEv6KMsuWfONNDJqnxP61tSPHK8 xZsPzYVh/e4eLujatUxI7SbqoIf7eq3fIwSwAge1C9g0BzblTefEg60dDP4fToAQFwcH1xY3Fyc3 BzfXVhhX12fGRVm5VYlZqUXplelZ6SX2FggAOw== ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2536715&blobname=ijmsv05p0273g05.gif R0lGODlhZACJAPcAACcnJy8vLzIyMjo6OkRERE1NTVNTU1tbW2RkZGtra3R0dHx8fLg8PNQTEt0S EtMfH+UEBOwCA+YODfUEBPoBAfELC+cQEOoUFMUoKdIkJdklJdAuL94rK8c2Ns4zM8U/Ps8/Pt80 NNo9PeQlJeIqKuA8POo/P6JsbLtmZrhycs1ERMlISNRFRdRNTd1QUNNbW/xFRedYV+NcXOhdXfxV VfxaW8hkZMBpaMtra9xjY9VubdtubsRxcc5yccF7e8t8fNV8fNx+fudubvxkZPxtbeRxcO5yce59 ffx0dPx4d/x8fPyAf4ODg4yMjJSUlJuWlpubm6aFhauEhKGPjqmKirSAgL2FhbOMjL2MjKSUlKKe nrWUlLmUlLaZmbydnaOjo6mkpKanqaeoqKysrLSnpr2jo7Krq7qtrbOzs7uzs7S3uby8vMaHh8KH iN6BgdSKisWTlM+fn9uUlNmdneKFheqEhOePj+yLivCHh/yDg/yMjOqTk+acnOybm/KTk/yUlPyY l/6XmPCZmP2bm8anpcukpMOqqsyurdKkpNWpqdmvr8G0tMK8vM2+vd25ueOiouuiouWnqOOsrOyr q/2kpPCop/yop/2rq+G0tOu0tOK6uuu7u/GwsP20tPC8u/27u/3Av8TExMrExMfIx8bHyMfIysvL y9THx9/Hx9LIx9PNzdvNzNTU1NvV1dfY19vb2+bDw+zExOTLy+vOzvLHx/3Dw/HNzf3LyvzQz/3P 0OHS0urT0+Pb2+vd3fHS0v3U0/Ta2v3c3OTk5Orl5ezs7PPj4/3j4/3o5/Ls7P3s7PPz8/309P34 9/f4+P7+/gAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACH5BAAAAAAALAAAAABkAIkA AAj+AJ0JHEiwoMGDCBMqXMiwocOFwqBAcSVxmLNhUJS5GuNszKuDoUIxOzjqizKBw1yNEvgKirCC r14OlKhs1ElnwkYqMxUKpjJVBoWZcjXw1cqDyqAsEGZgjYKOCcIYUOCEqjNlCdSESqAMAYJXTdQQ HKVADZovTEw5SeCM2IFQXzJ+adJkzBomUAQa2NrEVRM0A9AogPLlgAJWX4h9AbAGCpoErqqaWqPG TJOeTpxBacLEI0FTJgMgWNmyiQADCxIccOYk1BoCTNYgSLDGQBNnpthCWSNwgIIxa525YiIwQRMo seMaQDASgTMECtAYYKLArbAmB7B+ZbLdgDAEB4b+vxoWSs0YYpPRjBkTytRnk2wFfinwJUGBUAUW 4M7PndVsU0zEJ5BbBoihWijBOaNaWgIQY0CBahgQnwAHQKGAKal1lgBYy0Gx4AFqNGEfFAgIQ5ww yigjzCsfPeTiiwYxkRmMAzXTTEO7YYcXjTz2SKONODLRxAJo5OUiiQis4QQxCITi1UcLICDGKC1q lkBEBa2x4hc+DpQAAk40UYqSTUCXkCtACcQKjM5BUYAYAjjzygEjvWXAGKYccIAwAzjhCgFvMYGG EwAcECB+vPnoHAILnKDbjF0i1CYTAyDgCgLKoGWAm1A4QeRfXyiAgFoJQGEKAl+skcACTnCp6HP+ CihQKqSRHnQbGhhydkCJCkKnhiuiDqPAAaY08coYX7pyAJmsLNvlbXWp4UQBjNZq7bXYZqvtttx2 6+234IZLo04GjXTQK6awkq4p66rLrrqqrFulQTcRZK5BxKxhyijsvuuvu/GOYtFB+a4xbzP7onHv RTIZxMq9NzK0pkGTjbGwMrwgFNEYxnK0EDHzEkQMiUcVNPFAw/SCkCkRt9WEFl+YcosegOThDC6U COQeQq607AwyrWjshDBOnHUcGmv8oscfSiwTzB9thUxQXbcRNMwrPRHUS8YHsdKyKSGqMkonSgyR RDNE2IzbQcw04zVBxciCENbEXAQXE8KgcYv+EjUocQwSNoOc0BejFiSMK2IRBMwua/Cr1RonsVyj GGqAfMwgt1jySzC1qHmQK2tYTBAysKgr1CuunCRM3QI1sx4xriQDyC+U3GJM54IjtACRnxfkyyw2 msJM22pCPFBOzixjjDPJDLTz5wsXo8nqVLI4kjANtzzMjcksv8wyUSOkzAISde27Lc6wwrrzLZsr jAJhOPMLEc4kAXX6Z/pcTCZtPS8Q9gMxF1a4FAwkLCMPUMudrRDgsaKEooECsUUsnJE1grytdQPi jDOOQYllIOF+/hsIMYhRCv3xr4LHW1/ElDGk5AFiGUnQQ/gQIiiiFKQZaRoILWJhivWxL4D+A1lD 3ZaRjGD84hg6IxjYFgYMSRDjZMdr2L1CIRNjGHF5CjSIEwighYGoyHMEocUmEmWyGwlDiKUQhiqQ 8RFjfMIZnbgFGD/nM2BMQiQGeUXdsPYKVghlGHULxi2a0YlfzPAgTtjR/3YGRWdsYhMrG0nROAaF AzghM3mQ4Sc6tzaCKCNrrliYLyJhQ8O9JFpNmJagnPFBZ1zCkFksCLISd5F1jeFGI2HGI51xIyA5 gxmSc4KhEhAmq1wCCb/4A/iAWRBikAJkofCZLyChsVPahnyxQoMzKJGEYMjwkAVRhhP0dbwWNTIT /DuI5K6SIhsRj5fgc14zSzEMYYTiJLj+tAUkmjE84o0kJm1TxghTlCJmKON7QLraypwgLBEysiCZ 4AQ+C2IKFrHIFRbNqEbR1cyJhZIgsuiDxqqHuo1utKIJoU6VUjTCUhRkEo8IBRrMg0JiENSmBM2p Tg0yjJ31jCCxEIQrDsciT95UpyxtZ4pgJBQyCmQSlaDgQnz2op6uwWebsMMr1uCKoSBkYdlqZB+o iUK29UhF6xTIJvzgjJIhhKrYKqVA+iCItopsDGKAwiiQhoZ60einA8nEHaRqr6ViUFvCYIVTnYGH PRAWJsLjZZc+OpBJDLameG2NXc6jLYOGsAiXNVwPa9SjYYzJZ304wmMJwtFfdguKxJD+QRHw97NV sGJgQOxRMygrEDoYwa4EEUYp1gdWbLEiFKUA2xoQAQcwgGERaYiCD9S1hlB0Fbl9DIUqWDQKKqkE t3O7lzJ2MINONkMXrAgZXK81jJuoQiYYFchQ0Zq6n7yiGej5yE7WpJGGzU1fk1lDHNhgBjQsYhFU 4EG6+IUudvUxXRetKLr8uq1hrGemYwiDGADcrw73S66GYx1KceNSZpSCKCQU3k5QHIo1MSMkv0wX uELoEBpX1cGqEIWOpSYueR6kU84AhB7yUItPfNPGL2LFKJLrYXYxucn+bYgwRrEG8CYEyZtpxiCK LGQkjMTG6XEIcJgwDEgV12QJYWb+QYZXz4a4lSBjyEstlqGHW3xiEEnkmUPQwOcvzEhJwlDDMv5w iUEcoxNv7KRBnKRBfEV5ZW8lSDwjhmThOKRxV0mURCiyzVokoRaZnGM4FUCZcI5BDY8+iEsNopSX /MESSLgE2cBnY1eop8YGEQMTlKHNS3jzzkdeGXeq1sxUU+wgTvnILwBxCUB4M8+9a0ilFYJkZajB wgQzNkUJ5rHudcKNloB2HnFtECWd5BLJwLMxOiFuemmTIAgzhbY/w5IVgWxFI/meHJ2xPEV78okG EYUaRnHqMUTuIGNYwEmcLUNj4Jm2BnHFl1xltZg0xKURUU9VFFCAhVMiD5pTW2T+mzmKNKzMrzYe w66dUYtDB2MZ7Pa3J73iVpkQI8r2fOAatLQ2ExkGLeA5yS86MQRKJAOEBokYiAeyah8n2UWJu7n5 6H0RZehxoANxGviaJ/NmJArEKTIFhd0ziuMQiVhPaQYSPpGEZOgh3DJfCOQYQcU8RjkUI8y73ve+ 9xB+EpoF4UUvyro2J5gCOEpBAHGc8QdAdEKQl2j3QlYt9YIQHmQmzbxFKfz3YbwZFlugcM+hIK0x jKI9AqlFMGYHiEQ3Uu4DirKWBqqMM/NoJ/KFKCQN8mZyO4QYzGCFHwtyAvQ0Lo3XArilCTKJSAxF X/dsa5On32QeL4RFUW4BM1z+4UNsnZGWAuEDH3bC0h6LMMoc6GnLcorLLu22IHZwbO97XPmBXEAW blWsGkxhBq1Y/yEgVgd1sFrYkzrtVXvcoi/+hQwRIAmigBTbVSsgJgRCAFw6UwrtYXrRxy315wyO QAF0QEv89BOvRyP2tFgxIAPO0HQiRE/gki8Y1VUoAAEqwAiiEApe8AEegAVXx3d5J1CGdX3wRgIw 4HWeNGIvyH35InbCkAZrgAyIoz6iEAarswZoMELsIVCnZnXWJTExsSKm4AAOkAqhcAqN8AM2YAir szqA9IO0J1C2535A9AqiIGHJ9REt40uutRDCpy5OwAqrsAhgwAitcAZZoAr+qqAFUKAuXzAGrhAK u+EKpaAFarBVyGd+1oKAVyFC5rJHFXVzGFU3wPdLS6UM/MQjzHBz8xZE08cvHuaK7EJ4VWVTIwRI olcrzdBg0pZ0L4EM/FZEzYNEcXcRW7V0yKYGj0N902eMDcGM21YQrYIhzgADn7AEuAAISfBlbCNQ LJgQZoAcRPMQ0zY3/OJmWqQAqpAZQyZDl1AD2nhlDcFnoTMjYVIKTrAMSpAHefALn0A/w7gQVzOO kkcMpOEMwZAMx7AMv2BIzvCAIDEG3YgQ5KRm4JgXf1BAjxdzAjk3uxgUHmMMyeBrxhB5/9g2EalO BlEK8bMmR+Rsv8B1Jdj+jB1ZEF+wFNv0CZRwCccwBLRGbTOJLwMTDALBdUjWU4cRcWZwkrx3EGqw IfLTCXkwCJSABDcybQ7pRRU1FEP1jwpyG6B2C8Hgj0jGCgOwBvoRbSJTe/VSbZL2S/GEZIf3ZtiT LzFRN5UWHMEwBJ2gB0MgauEkDBR3EQOzdLGIjGiAMAIBBXFmCmCgBl8wEls2CEYUbAnRjamwWz5U aQDkDLcQjJInEMpwGE5VVMtnSvTGCmqgBaagBaJCACdxC3mQBJcwZD0ZYu2GCBaYRJlCDGJADAaX NZ0ZeZagkSsjBgqweCyBLmtwkmW1Eiy0FlAgBmFyEkQwm51ACZRJEO/+1W5yYHGf0QwTEQYqlwAB kjxEAAiWYESulxAvAV7jkXswETIbeWwwcUaYRhBAsFhrgwa7Mx1NYBVBBmu1MAhvqTEDkAAQRJpS g3dXQTztoYwQGnEiVhA60H3mxUtnFk9OFxT0IlCJZTjo4hpWuF48spW56QwvYFCnKBC4AqHKCCNG 4Xd1I4uRQgzNEHYF0QLoQTlo0EhxeC0gxgtzsFrZMib+wwwi0BbOCC4h4wg5sFpjUCQ6h2pd4j/K EALg1GNCEUJ7gKU02ke14j/IMALCgVumgAZiIFPV9X9dkoogVgQSUBOkhROj1SX15D/FcAHKwAp+ 1TYEaYo/GilWygH+FIAKwiMMicACP1B3tQKGLTMLFbATC7N98ymo+iIKlNEDOHAFZ0AGXYADPbAD VsAv8aKVrBCDrhCDyLMQ/pMIEzB45jIeGxguE5Mv/yNEwnFVxICMyKAMy5mKPXoVauBSPcWmAmF6 ojAmbbABV2BgaSAFHWAFT6aVqXqqMYg6FsotqRoTriB8q8gQO8MuAgFjw2Aw6cNZoyAWyoAnV8Ee cpJe4dKrbph3yECLxFCv8nqLLtJgqONg2wKGDlGJF5VR10qwGEWjh4WJCHFz+glpkIUTLHcLndA9 +2ZjwFRqDCFQ90qv9ipQ9UqvgYoQMZmSBlEXCDJog5AHMJSdKMn+EPpyqumleRpVqbcaPz8pEExQ AOB5dJbwB8YwZAJxleEkp+B6SUryP6PADB/xeMagPAxJs6Q4nzQmUJuIRN/zPZ8pHA8kbVDwCopU NPboDJozBMbwB0jglw7xMBeXdBQhdG7kNICQtXL7GYmSKE1gACPjDHrwCzWwl0kwt2dCL6GANftC FCFkI2pwAi9xCZ72PQbElXH3TgPRe8pgESexTFcLuEHhmHBlo0JkU8M4BgrwEpC3emf7j4ejn41D GUijZgdxa4P2PZwUk2fUJFMXcf4FtVlrdQ3rulwpJJypBI8Xt//4J6FAbC8Gn4u2bRvTBBgyCsSx DIMACEowkg/+R2M3+pklRHWIRBwFNGdwV20L8IhedE8EqU5jpxmmIAZxlgDDIhCdcAlQAziS53mS 1wzdqLsQR1Eegpx/9woKs2b66R4RIQYL8ATmoU0HNHTBEL8xhi9DUQrvViPbe5pOwDGmcBhNMDx6 UAtxSwnEyZFVgh5oixBKyar4EkomBhMR6VKGVyRVsSoCoQeUoARupwQlvLCMVFwa0S8fwWEu6mGv J1ztVgZw5R5+ESqOYRfwC5u38Ach/BD5MsH2QgyhUE/Z2iMjJBDduATMkAbloQa8ob9Q61n0OXIJ GykATMXOkAMHNxAPGsQeZqx6VhA2oKQ1gj2vAIT66iJo7Az+LuCL80erYMUBveCdV2EKRoorkFOl BVECKlMyLxYKYmAUrKAKIQsj5AF+v2QBjqA+eVSnPpIibzYCu5Cb2JNY8vatPcKnVjMBbsAIvZQI hWAUVtYjU+ZUynABkNR7MvYtSraGr+ADEQACoSAKhrACEBABDMALtThQtHiAtNjH3OsMvDAB+5Q1 D8MumazGQ/EKYWAwrgAGYsALrqAFaPAKiTgGQnFqfUSJLBKdh4MGSzquJ9ZVXfAAKEB3a1AFGWAF 6dWtGKV5twwjK6qJvQqaArUv6aVY8najK3QTQXhlbWNh/ATAdnlVzYAGInFGSJzOwqEGa8IuWYwt w8NL7hT+LvvVRzmmCgWdidLWLu6yLjStLvDijHrYEOCzooj1QNSsuS0LE6FT0go7EKkDrgaBBn1h kZTwB7cACki3sC9dEC3aL9MaoS+iEWrw03HnBGKgFs4wBEqQBJQwCI9rsYk11Z9xHUxADJkhOIGk kMnTb7q7p42MwpbXBLY6CJ8ACBJLvDZGQrgKrsKwHn7mDE0gBqLQBMtAA3mgBLXwB3+7vy5y1JNH I5pJ1M5DQpmG2AZQZs1QNkmwl6erv8JBYStidVJnY+AYZJegBJ9ANlWZEHrEU+10ijQGO23BDC/3 C8twDP0Wk8yQAMZBL2sgBqgdo+riu0GkAMpGNoNQtp/++UmcJTLpwtFc1XVw3BPLYAnNwDlyKypG smZ7DBIEcZKAORLHEAyU0MCD8I5JV9uLtjCVtgBemQedINlZ6zqW9IyWzVq5SyO9Z0OrA8HPaCtP kZd7icOUHUAHILpZksii92buMQxNMBf1sQDZEWR5sASyxuA0FsDCcMsRGUKZDLWMgB59RVFR5h6v ECqNGSUGcBL9WGjPdqLOIERWKBMj0QyJ1Tan2AxJCxYh4goL0BLNcAx6wN6udAnw3RD4K19cvTP7 9wXprC43AgojuW7Xe0OrVuDBRRKscaZi8J+xkjyXAApxGwxqM7IIAUqix30VFUr3hFR2rlOHmzVg jjL+N2pTuI0bTuAhThAGimmQRBAMr/RqQB1OlEFh+LXKH3E4MFutk16tAp2qFuqJVmYIT8QeLSZz J04jyCB2BZEKDcktbmMK4NUMOHARcgXEcvwuJUphP4DKh9MM7aXZDLHnF8ECOOFf/ESi2uLKXtQC K/gZPHGm3dUl8i0Qu0Cm3FcU6oGMZoGwXeKrdy0QyMABQp5b6CLsDjHJPjQJF4AwotdTdQPukRLt AyELcZo4w/ADjSDK7tfszuAGE4AMV3kj+SUuisVkpZACDbAFZVAGW/ABDYABjZCq23pR6oJ9mwkR 9WV1LjABiqAKN/cGGvAGLGMjKb2H2YI9NoIGObFpVffFCgbnOpATaGKH8sB3eCgCYx9TXaEQBmpw CIQwBbtxBlGwBYnwjewxBqlyeF8QCulqF6hJ7N2CQzHbVex+ezcB5gDEDKsDO/KGDKcTNSdRTydx c93sI/dy0uEyQrxQT6/QCkHjIgEBADs= ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2536715&blobname=ijmsv05p0273g06.gif R0lGODlhZACMAPcAACcFBSckJj09PTMzMyEpPBAQEEwQF3sFB24KC1EWIHIeKmgoN3wpOB45Tiw+ UDE1RHU2R3s+VVA3SzlJUzthdi1WbEREREtLS0FRWlRUVFxcXFhLTmRAU3JIW1BdZ21SbH1ZZl5o cWRkZGxsbHNzc3x8fGtweLcMDIIiI5U7PYUrNK02O+EdHdQcId8xMd4qKvM6OuguLYszRp0+UYRG WpxDTq1OT7NBQapRV5ZZaKpaZJVuboJvcJ9+fox9faJgYLdnartrdbpwcatveddZWOtJSOJHR/xN TfxFReNcXOhTU/xTU/xaWtppacd3et1zc9Z7e8FtdeJpaPxiYvxsbPxwb+N0dOR7e+h8fPx2dvx8 e/yAfxpcgBRolTlsizVsi1F4l3h5hWt/lIB/k4R/h718gcp7gmGAnlWGpGaJpmeYtHebtXiLo2uj vzORwUWYw2mkw3iqw3u83HS11X7A4YSEhIuLjIKCiJeKjZSUlJubm5aOkq+MjKGJiqWQk62XmLCe nr+XmLSNkp6gn7qgn4+Zp42gq5yrtYykuaSkpKKmqqurq6Oprbavr6ezubS0tLS2uLu8vLm3uaet scyHiNeLitaQj8GbncqZmdSTlNOdndycnN+SkeuFheiIiPyEhPyLi/2Ih+OTk+Sdneubm+6Tk/GT k/2Tk/yYl/2bm/Kbm/agn8uursilpNusq9ukpca1tte4uOKiouyqquempv2kpP2srP2op/2wr+Sz s+q7u/2zsv27u/24t/3Av4auw4ayyJy4yZq/0qi6xLS6wbzAw7rFzKjF1bLI0rfN2bzS3b/V4MTE xMPHysbKzMvLy9bGxtPLy9jExc3P0MPO183R08TU3NPT09rS0tvb29bZ3OvFxevMzOTJyf3Dwv3I x/3Ly/3Qz+HS0uzU1Ozc3OLb2/3U0/3c3PHT0/3g38vb4tzf4dTd4uDf4Nvk6OPj4+vl5ezs7OTo 6vDj4/3k4/3o5/Ps7P3s7P7w7+vv8fXv8O/w8PT09P309P7+/vn4+CH5BAAAAAAALAAAAABkAIwA AAj+AP0JHEiwoMGDCBMqXMiwocOFIkaUeFSMor94GeDFu+AvQwmB+/b5e+ePxCJm8UQSLKEhzz+S Ev/5yzNiRDx/+/jFu5ZIp0ANIuo80haP3yOU8fKQsPfvZrw9+/SM9GfvpqRIkp6JTMTsWTZtBUmU 1BNpkaR21zTAK5GBnwUNFzOI0HMhz9xEFz6+5Ketjr9/Iy4w0zBCJlx+I7KR0JAhkh4LFvj5E1Ey D946cy0sGhG0hIh/IgQ4qylRA4mJjkvo+adHWwmJBUe8E5FokJ1FJRQ/sxCgGU1+inHXSTRiEG4L TUu8g6ch2yINdphFlJnh3SBmFiJlOJpHQB2SIt7+tZREwkKeYpQ5awMq3eYIDc8IA5b5j5/k+vYl E0xUx9nMPANJItkj/iyyiECLJLJPHdk8Mk05iRxI0DN1aHONHfEsQuBIJaBkwUjxvPNMJAD6o0cd 1zzzjh5DaejPI4/kgc01eTwSyTOPZFOHOwT2CA+JiWz40JBEFnRUkUjq4dlcUg0ZTzbvFPXSPtm0 I1A77fCjkkDxOFXQPzLdhCRB/2DJj5VFuVOOmAclYsc02WSTCJGLDKAUCY8MEEkJAUgmQAkl5MFP VxtpIJ4k9pQzTSQkiKCNCPFIMqZAs2UwTQHaXHBiBn5NClFJIoQK2jPFMDMAYSVsBt9i2lgwF03+ i5BwwaMaaOapM1LJpQEgzIyQUH7ABivssCLwQ4JdEZGQiCTMXJBIBiaJkMEgEiXC5AgCRFLTMxHV wcyw4A7LjKCh5VHCAFyB6+lA1/ijjT3ZTIOjJDJF8gg81/zzDFgj+oNNlCn+w8w72VwTDyzr8kMS NtXEUw0kQ60r8cQUV2zxxRhnrPHGHHfs8cQ3PiPyM86MLHLJJI9cssQKQ0nwOy+/g2U57rQjM5bw JMStCEL60469BJGEkDN5kNWTQ88oJBNDXkHZTkhQRx11l8Uo9MgIYBWUtUBbG/SMHvEouw9/z9jh Tz9M2ALKOVrgIpB/By3KDEHZIDSNHn9Istr+P5E8KRM44HxTzz1u+5N0QsM1OdA/2BCEMELPLFKf gHro8bU/53wyRRbmgKLF2wp1HY3deshTh0uLjPiZP1PYkgUqt1Qh0+EIJVLM0vw09UgjBLWytNcF 0aivQKmYUzwvvAhEe0H6xDON43ZX7c/ckNhRxyCSoaJFFqnUosU5hivk2ZwXddp1K8xE4gwzqRdT DDbLD6SwQPT4Uz8+9yhvUDbyvMMM3AK5RDxwN5D44eQvAgFTP8CED/0hJB4WGAH5+DEIrhGEFv/6 0Yy60g4D+gNQ/7gHKqawhc59AnQFwYaEGpdATBjnHSQyS+oOAo88kKQXvLCFOeixin6ELyH+ehjB hrSRh35oY24DcQU/njGN36GwIItYnRZswQRvhOJzPyTIES04EE0QBRvaeIc24uRBZtQhaZ3Lwidw oYV0ZPEgqWJhhl6CRIFswh1OLOBBRHS2XoTDG/Q4B/jeKJBIRMJ/APRHJvbhjLoRpF1e85Y/PpGK UOBiFaConwcHkggBIJGCXBRIJtQxNErN7x3/kIdAGtjAftSPkP5wxu30AUmBCAEhtRxSIg1SB8cI xB0l6holSHmQpLFvEZXTFEf8QQV6UMEfWjghLBskkFwOIY8OTEQejPOIEiSibuHohS0EGYr8bVJ5 GBII/OLBjJ6ZQRmljEQiTjNPEXzEH7X+wMcp+rEFaRowEkhkoUB2gE1/tOsfebBDNop2gRGMrh6p 4AU4UtHGWCbEGXVIkEDgwcJcRiEZkPsLMxrEjHbAQ2j1S0cgB7lLf0TjK10hSA70U5DDLSIPeViE PL8pEF4IkhenaOA5p0ECO5CvL6H0RxCOgRBJxGmMcfpKVMcIVajWcSDFOFzXaLAlgoyuSOf0Vx3b ISnGEQQIx3gGcNoRD3iIREshsUdc5xoSnchVJ9ichoS2mo+DaKNkKEsZYAWbsn455B3T4Ichz3qM oyTCMTe12DWw8Q975JIGY5THNaL0Dpp+rGs4EMZICjqxdvSPGXX8RwS0YS9AEMMyEvr+mLsIgoNg GNSzBi2ZTqcBC6iyiUgC/QcE3OGPcsj2S9pYXg2AMT1/OLKaR4nENRZRqiCFNXSLgwApWxqPMG72 IhmDx/JSsIZ2QEkT8DjTjHDrqZ181R/8WAApmfGP5xpOQ0W7aYz0ENuJXUM/8lBAGEZhiVHAgBXu 6CrFmrK1eCzAEWLMRib+AQ9tYGMf/3grKvHDXk9pIyvNKMYO6tCHP/zhB35gBIyYEQ0mXmMacMIG jLURDaE9BIDQSIAgRFHgF4TxuAIph0ze0Th+TIMk1wCLJEqwr9s8o2hnKUbdtNG1hqTvGsyABQ/2 0AdCCOIHipiEjZj4DDCW+SuTTW7+hzP2DEnYThI2ksRJcjYpR/6YnZJ5hpUeoYd30OgaC73REQf4 XSAbWiDFOFFZ+DsIPSjit4bW0FEeYbJKW/q6DYFHYC/N6as2hB/XENBAEhSpRpSqGDl7ch70Bl+S 3KQf53ClP+rhQ1huVGQN0Suco/G8hpxTRLkxSJQG8oj/LsJ/XRHJk7NROX/UQRHj8gcvlnAKLfwj FalwoEGasrxt2C0P7TCqV8hiB5mgAqi3CEcotG2QSAigGCUiSFEGMrpcFhCJSbPDBaLiD19ccQn0 AEXyLJqQrm3Cbot4UlYtt4hyQzMUq8AHLrJQv5YOJB4iQG0CZcI+NsUiRMUsCJH+p+IPcNBjh74w B7vlDWeCHDxuTnxHHhbrj1vUohf/wMUnhJoQSUxiBGa7SInmLRBXbNKDoRYILupxC3+YAxxP3A+Y BOoPUeCStAqx+EA6Kyn4Dn1LrvD0QCxuvRD2YgpaMEcotrBygQS9a5VASDWw+Q6T+MMWWjjFKeqB hHrYml2DYCERncsMe3RxzR60Fj/wQe0t9AIU0uSuHSSztX9Ageg0zZdB5GEHqdDjFKioQjg+0XSt +0MSF6hDk+IRiYtcw/ACsYTOEKKfBfrwdx7MA+uFZHnH8CNCBjJLQRMBFl6kYhfeMB7PEfKPRouJ H0Enuj8oQVr/LJQZe9CGHeD+Qb5b5PzuULe1wyv/hKf94xFU+hd9L/KOfXQpSvq5Bz18OEhMD2Sh XGKTE54E3gmZyBkJUgeY4Rf48AnpgAr+kAVYZEBJIROVZwUi5URN9A+30XB0UQKjwwuoUAvHlwVu ZH9c03rOEAk0FQTuUBa3YQdFY1HMoIIikFM5JRBNp0OnYAttB0zqtDhNwE4G0UT+YAcWkAiVAxSH kwqf4Au1kAXgA4IjUQ0bRVNAgEd4BF/18XcLwYAGwwxddzZS0CVnQxA+2A7JpSIwox/0wAs7FH5M +A7k44UCgQN4tA4FsQ+BYgcmE1iDlYf2NhKSM1sCwQ9SUCDRYDs6lQg+SCT+TAgPByJG+vEPNaAO +yCHBDEIzCIC2cAMgwAL7YR1zNckW2MPSTAS0ZBgWJIlLwZj0VAN15Aiq9iK15CK11ANVRY6c5MN z8AmM6AO/RNk7SIv/pMNjeQMMMaJB4ENj8AP9tBrVBGK/qCMh0Z0/yAD6uAON/ESGjMoj0MVSrBy yMZnMARG2GBfE+OG/KACyaANueMxWzMPRrBy7ARQzNIiZSFZkQB7/MAAwqAN/6CPHbM15LACMuEM dBYNL2YlH+OG86AAbTAMh4AMw0CMk1JfADQOKkB57QdfhhYPxeAO7xALBvAGdCAHEKAGwYAzKVFX +VEfYAKRIrd+/sANClD+DfZRCa5waBcRDe3QTuXwDIowWYvgDOWgU87xCOXwCIngP4bYIExYQCqR CwbgCplQCUXwBDZ5EEuzNIsggMGnB0blcJOCDQDFDJewAXjAB3xgAz/ACGFpMrxGZRY2RuWQDSwp MdewD511ZDJDJevCj/DjDz9CEtLlD46xD+3QZ/4wCLfYIIA5i+3VDsRlYwTRFZw2mfuyLo9gBxPB lXawmXYAmRcjN5d5mSuoPIOQCNhAPr62Lk3xP6jVmicjmSLTFesjdgvhP49wlX5JH2BSQDO3gpd5 DVLxD1ngDRTXD6cQdUGjhb9ThQZxDc4QDfHAhEs5EO3wOyRRUM+APe3+MCf8hSv+kA5ZsAvHeQpZ 0HZaRFP8oErNOXOVIxPGUVL+4A240Au1UHKaNJcEIWQDAQ36gk271II82A+hYA6+cA7gUJ9W6C4N 9IeQVk1gg0z6YpQzBAqhUAWo0A9UAHXTyQ8+9zux0A8eNJ3mCV9GiZ4N2oxZY1z8gFNU5g86Vwu1 4Auf4A3NiJ/rJ5dJJEYHQXZ1EEKhkAWgYA7egICwxCboKD+wVxCHOCTnFDkZNxCT51y/4wq8E3IG sRnZQ1EqR6QG9AxHhZ7iKBBLenExiAunAKP1EAoamhDVcAFuNmrR6ZL+MAvGZaVKSiD4kArgcAvn 8A/1ZxCsxTjFQFP+8cAKZqFCWsgMbJA/BcF5B1KAn3BCtaBy0cCJ8bAhK6oTz/A7GFRK7qKX6GiQ +XMPIeRGsIQVL0GCAzEPuWAw8iJep1lrBLGiVYMLqNALOPQJS1hwPCMkgjJaA6EKVEcQ/lERCWIH GaAHGSAQVMB4+JAF6wZLGucvNAUPuSAQcloNtYafTboIexB0/5AIN4GjAqEK71VT/gALQSRBniEW +IQLRzB6/mQQP8I1NEUOgbAPnqZ5J6IkebAdUmEOW0AFu+APoKChpLUPTCQ0STEotzkQpkAMz0es 6iQi/+J+AlEP/1APHPtKLWUvirUINDUOfuCM1SQTXLlfngEIAoH+Cp5zDkeQPOcED5pyOKAmE+vw O6ZwCIugDchkHHrQD6anEAY0UvY6ENyAB9rQQcU2I5HggIVoYUkmEE8HDjvkd5uaEDF3NPopEJ5g CPLQXfHQDusQJXoAfMwiLzA2DasIYy/2tg06te5CU9xwB/DQDqmDiW62ZkQ7JJOnWb/jCWxgUCl0 iWbhLWdrHEf5EPJEFc+gDwOxDWEgpvJ2aZtWWCNDmwgxRgorp51wBlkkIkMGMznxLQQjfQxBY3wj CTa2DSaArXtUFOnIt0TyD5BErv6ABaB7OCd1MWPENVsTCyEAu13FNxqCuAlCahTTtf5gBWCwRH7Z j8HrAfD1X0L+xgzYgA01sxxFYbrakF4Tg1q/47zDkw0nSjHpszWsgAHw1SXEZWhQMhBE8AXM4A7a 0ASX0FcZwxfKSAgTEEbyYAxwgJ8UY4sgcQMNMAqcUAkv8AFxQB8YA5a72QMPYAyH4Ahq4AB1elzA qIV6AAuQUBvMAAh2MAzM4GhtlghMZDuXSGnacBS0WxCXyAzToAjJawfFwAglAAiLkgjOcA2GBIzS lQ3NMBTZwLqquTTq6YUvIRN5IBRl8QjkMQiPoA+d1b5DYh8C4Uh6CSLTowddYV3GAQvT4Dde7DFd kcYjFQlsu5Ju7MYTkw2GxCz/UxZxUpVCCMaJUA0M07atuLb+bys9VZnFjMglVRK9TmQgewCc1Ru9 Z1MP3/Cdf5ow00CQTKS2a8tEvKa2vFa7ziM0ctNwotkkOiUyAJJTzdApP7oE/TAFCKp1FYYSQXMQ /5U796Gbi4NAs4Mk8/NIByHL1kgTJzxrU0AFnwBU5fl39UEwBAENtKyC4+JDqcNWAvEN3wB1tfCB RdJONmZ4HrRL/NA4YtIP+GAO+MCxyFkQwEEQrFBMfUYCqzFdyIRGU/AJWxAOUxDJY6oQKqETNoZK jGlxkSMQq/ANpzB/4WCeJAEj9nWtzbkhrRcPJUAC8uKiUwAKApcFMvsQWfGHNrZedkoQZYcPvnAL CDhR6fz+QTKxzklEy3kEkUz4Px49ENKwSRZHLYt3BOBwCrGWbQRXEKsBX8/1Dy8XPNi0onPjDbVg 0gYLdZpXTImgAa1XIJISOTYWC6QlorBkOn841JRAMtGZDTTztAYRDxk1a7rKC96QoVY4DW4qIfDZ agNBC9V3NqYprovwMzIIDqhQP5EsfgKTIwPRD5QwFOxzmleDTWZNILfwCbvQD+DwCQmdtQcRDyMA xNWkqr3sD7IAuSFXbNRlBxpQBxzRD97A1LyARRbXhyztD/rACZSyJU/NpD1HHnuAIMWQEyAnEJ0a ctOAmRlgPSVgNvewBHx9DqjwTEXao0I92FaHFgQxdwX+Mhy3MQLs4w+7AAq7EAoYqkkK4SUFohHT MDADQQrR0AwOgw0489P42VL+cxH894eeoGdKirIqrIIkAM/+cA8Dyjla0AuGM5dHJhmbrQrEAFCp Q4lSkRWUWWko01LwUDUiY5AX4QRR0sRgkrXjIoSo1dG7kAq2YAvgEAre7RCpcxObbQrDQLhkAkbx chH3USQSvdLPdQ9OUDA4NQinswcEPKLFlDTlUGj+4AmIwOJbrEIGUgKRYAeT0Hmd8hD+s9IUPg9B UE0EkZOtmeWtOZuo9Qyo9bBWBhZiZGOdsAb+4IRP4wyQNkC57CT0ZWHPBQ85ADrnyzGbjQVm/jx3 rDH+5vVc5EADyvMPQ3uNNmYFadCM/oAJHVNfA0EOHfA2/BALBCEPpMIMjxVqb1nnQ4JlNvYEaGC7 +WAEWv0QrY0OHAAmKNEE+gJGT5IVJUVp7SQJjMnLW9MEXgAJ1RAJLIAM+osx/7M16CABKC4ORqBg HqNYkrEPN8AFwCAHa3AAXXAMK4kx/ABA2/AAk9AM0/AHLqDp+wtQjgELyHDBzIAHhWAMN2VIjzWI kXBEi7CKxUYkRgF7m0AAcjAHc8AGCFDkhnYfQjNsdnl6GTUuBqKCg7BZYJIS8s6aiQALjMCQySAJ PlAIODIIxRANkuBUVxYvkRAnh+QxMDXez9CK5vv+xibPiU1xtPvAj9mQM8WQCJulB+9jI8dIZEPm 7d+NIzEsEHxGFoMQDZbMtmz7ikIfi5o7JJhoB5HQCMFnHDtfu7NeU/xVG40sJubwDyp3DiqXoA4B aphsMvIiMjCmyRWNJGFaTODGajViRv6AD7fABKfwDZ0zovxQYTsPaNkAHMsJwQmEQIN+EHYsENHw LfBjUtWpPAZJEsJcQRiK0bywC1uvdQyGadOQUxBaIM1gvvazC9aMT0KFnzaWNe4TFZGTU44UP3r/ auZQD+dwD4xqa0RnsnGjezjFOI+ATM8DDqCwBR7YNlxfEOnkXOoc0vRWpbeAD+HwD+Hw1x4kczj+ cvQFdDhJI9EkkCL4VAWn4NifAOCUbRD8EBHx1hMhIo7ZEKUUaxB2wAb/gA+8sApLgA+6n9JzZGQM sc8I1ObRrbWcISHxMHn+0zUAwQ/bIH7+Cvrz5wzhQoSARvzDdyTVFF5bQiF8xnDhNT0YNX70F+0f yETZEH6zdateKnP+MoL0t2+RhkEL84z8Z3JhNX529vmLt/AlTKJDGbZb5O/ftKMFDyK8NlLjuxJJ zU2pZ8tfrX4upX6Ml0FSnYWPgvrTidDZvj38/p31t4hfNjuL9mir4ywPwlDgQv2jx0stSH6L4j1i tlBbpEfP9EQatGiQs68L49nZu2uKSnOnPBL+1Zivzj9t19LyY7rIHr93NiWVyFMn0h4RdTL4O1dF SxZ66VIN/ohtrz+mC9/p09YOW/J3IkHDNPocXqS38dK+JR4PnriFSdvp0TMizyA9SfF9SrXF1z9c nzVeu+ZeKcZ2C6eNZJZHUqJIebAV88ebWm7ppZ9UwPHqOcuKkeo0bbJ5hJ9WRhFKQZCiQ0ibZ/hZ jKF39onkKeJGKu+aOvIQoYSa6gnlHM9s2cUlCxGypw59lDqtNZN0uWKhSJ6Z5pogp5kmGiGFJBLJ IDH0Bxs7WHuEIXGy+eknqEZ65MS6HtEjyltACaUWXj5BkEmY3nGGH2YkSYucbmQcRYoZ50T+KJvE /ImEIV0kueaRPBZJJNDKZjSTsGdw0mYhdHKR0RMi6JzzmTvzXEgXcfhpJpp4tImHGWaeATVUUJ0R ddRnnIkSUve2kUVGK4oQUVXQtHkkVYRmGQehxAaVFdJ/7vRHF1G8SgIGeHqdkbqFaIFFV3/i0ygb 7X6KFVmEppF0oVmgQCsbJVpYxloFQ1yIlEKUOrQapTbVxtNI9CiBGT0k6bIjcZWi1B9SQIiEGXhg QACOe4niR5LWECpFDH7gkbYNfq6JR6p3pLXuHdbeOfheRYr5FIgAhIgCiBMAqCBIUrVB+Rpt3omn ZZfjqfZMZh5hB6F/PBGjGGOuacYNdwajnlPNlhPRBh5n9Jh4kWfkeSSReK5J5Bl4FjEsm0EkiYex mImChBorn/hCDrHn6MIJoM92aRFnsGkskkaYWeRYZB+xBhJ1gaAgDmCAUaOCGmAhFVRtlgvywWwO R3zrs6eB+xlJfixGkmes7BVahrSZBKFIFHrnkfimieS4Zxb5afSCPkU79YHzy8OORBbRw446FgFW ddsH3gfmf+CBGWZ+FGcoIAA7 ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2536715&blobname=ijmsv05p0273g07.gif R0lGODlhZABGAPcAAD09PUVFRUxMTFxbW2RkZGtra3R0dHx8fJqaebiCf6Kibq6ubL29ZrGxa7+/ aqmpc66ufLCpfrS0fc+bfciodMLCasTEdsHBen9/mIB/gJV7lZpymph4mK51k6ZwmK5cqrZdtr1U vallpaJsoqlmqaN1o6dvvLFisbhtuLR3sL9/v69+wclZycVkxcRvxNZx1th42IODg46FjoyMjJ+J hJODjp2DiZCQhZqajpGAkZ2CnZaWlpqakZyWm5qamqOKibeAhLmEgaWejriehb+Ui6mphKOjiqmp jrOzgbu7hra2jbm5iqKikqysk6Cgm6urm7CvmbS0k7Gxmo6Orp+SoJSUqJqaqY2NuZWVs5ycs5eX u6KPoqyLrKWUpaiQqL2GvbyKvKadsradtqSkpKinp6urpaKiq6qqqrSprrq6orGxrbm5qq2tt6Oj vK2uu7Oss7qvurKysry8srKyu76zvry8vMyJhsSRjcSOkNesl8C2ltiep86issHBh8PDksXFnMvL n8PDocPDqtbWpdjYrtvbs+fnu///taWlwKqqxaamy62tyba2wry8xbKyyrmzzLu7y66u17S007y8 07Ky2by83MGNwc2OzcCVxcmaxMyVzM2azdOF08WV1NmQ2cSkxMesx8mmycazxsK8ws2yzNan1tKq 0tGx0dmw2fSL9Ou768PDw8vLxMTEzMvLy8PD0srK1cHB28zM2dzI3NPT097e0dXV2tra2u7uxOPj 2evr3/3908XF4srK5NTU4t3d4tzc6+nP6ePj4+Pj7Orq6uPj8e3t9fLy8v7+8/Pz+f7+/gAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACH5BAAAAAAALAAAAABkAEYA AAj+AIkJG0iwoMGDCBMqLChwocOHEIUJVEaxosWLGDNq3FhxIMePIENS9GhxhysCA8bsmOGDQIwz qwT4WBmDgI8DMVbVOWDg5o4YPmbMiFHHwA4fY5JZJEmR1g5aY2K4WjWjjso5gmLMOIOU6MxVrnz4 iDPmzBikZ+LUQTqGltKOwj4SI3ZL4txbDY8JO3ZMWV29A4kl4/uRqbJkEo/ROnbrFi1bv24lczyQ VmNht/iuwusqMC2DtIhdNJyR1lpaW3dY3Xp2bLIDaaFaHUO2cFyOwnzEUDmjwE6gBrSOUVaHwIxV AVZpfWpbpPPncJ3fhh6SNPXrGK1j366MpKs4xPj+ih9Pvrz58+frNp0b/lj793zDw3cff759+vTV VxTNHfvnkd31599txGwW0YEK/VLQf/sJeB2DykxUESXGOAiSfqF1huCGCjGIGF4SSfSLLL6EOJeJ ArFn14onspfii8R0RtEtAVLESy845tgLL5XoyMuPvFCyHYMx3obMWxQBA0yFyFB0ZEXJIPOkRVFS VKUyUzYJYY3XGbMjkhwd0mRT07nHkTHDAAOmgwzGNd12vvAyDEe7jEkmRce44tgttjRmmWV83gJL LJC00tiegfJJC6C2MGqZLX0CKqMyrhQI6J5/Hrqon5ge2icsiSzyKKC0FFJLp5+5UsdILrbqKjH+ vpD46qy0fgbWerTmOqswikziIi66uPpZHZ3FcYsryCar7LLKMsIIFsxGK22xlSrzWS4DKXgQtgVp SxC3BMkyyUCGgLugMLSsMtKh7LbrrqetwNIuMO+62xmyjRATxyr8ssLvv6uMAvC//g5s8CpZAFKw wZ01wkaBt9RRh04SS0zxxBZnXHEdbrDRiMSCVPxxyCBXvIowE1MkyKIsswxpyzDH7DLLhLghM8vC COLKYMJM6zOzrTAC1rKwyIJs0cmeHMfOxLkCC7K0TBu1tE9PjewgrLjSRivSCtPIKsg4FocaY49N Ntllx1F2WmmpndYccZBhxRltn82G3WQLIsz+KqYRQ9vYMIAh+BdgEG4JC4InLjgfKyT+hhhvxIGG EmpUzkYVWdzNBhtj37uKYihvLPropNfRCMmCrNHHxaQ30krPtFB0RumtfyzxI5lIzAckn2SyRx58 bKLJ8Jl8gcklG3cWXjICqQ232tBHH8fz0sexRhpSpLFG9dyr3Qi6t/09/fNwyKG2+XKYD4dacbxR vsRr+KHH9PRTb4YJ0BN72zGbieX//wB0wv+YYIQGGOEJAPSfABPovzrcJg7CmIEAJzhBK/zPgmJZ YA/EYgQJFGGCPnCCCEFoBQ2EUCwns8gt6EY3MpzBhTAkgwzPIIUaSuEJLXwhC2VYhhyy0Cz+LHSg RXygQx3OMIZnMMMM6VaGJCQBCkrsoQxnWBYgFpEMkyJGHW4xkx148Shf9AEPFvCAJvDAi10EIxrR mEY1HkUsqnkTEekWBSUooY52XEISLuDEPvYxCi78oSAH+cNJzUgsVgChAI/QBCY4IZGI9EEXuNAC LnShCxl8ZGtaw0AhKmMVxNCKUBRwg1LeYAalnAEChMLKVrrylbBkZQqVoRjUoFIGG8jBD35gAw1o QAcoGIEvhymDGRTTmMPUAAdAMJRYCgWCFmEJA6dJzWpO05CMeWMPJsCENzLQm/4DIxxnAkdxklMs nqSINK3JTgCCc5qz7A4Xv/nNd3Zxmvb+FAs0/eI3NdytcmdQA93IdoZ/vtCfZ6tc3AIKPYCSAaFx YNu+psOfjKypInbijnYuiifCXGQwF/XoRSraHTdd5BZ8UMtovpMdZGVnVRhx6UgwQ6P90EItb7IW KDFyrL5cxBY5pUi1ZiSMOBgAO8lQCn+YR9LqCAMl1yGMR5BBjNBAZyA/8Sl0aHEGVniRKwcYznMG YgACXCdiVRnDGOoglEZclUNwfYhlDGKuuHIoNHbN60EaQhBv2bWuD9GPhbCjnY86ySJHyqiVqFNY ihAjA2cAQAF2UFZWFEAArBAKAQ7AkzNo5QBbGQBnYaqRxu7gAMp5CQF2YJy7AWAtM3D+SQZ0g5Pd zAAnO+CoY4P6UfoQwxjtCdYx0uSeuRRXPvTBDW9HqhcahUcyxhApYXKxGOks1yIoaUlZfWCAAxQA AwZAgA+IIQACqHUAdYgBTlzRnI+4giurGMAMzlKAmwCFDMkwwFZmMoYDmAQkEqrOYEdzXYsOODoH ZmyBE6wRCempPeghD4SjC+EIm+cWuaAlKJPKl8Ecw8MfFg9IRRziDo/HwyD+sIex5Vi9MBgkHlrw i/1ym8ro6sY4fpUhZfxi/RAksTsqxmGOFKUoPSmpUlJKkY+cVKUQechvkdHePlOXQNH0ylVuTC4i E5m6YIamVf7yoWgaGQbx5U3JAMb+jXAkZAYT6U090lGOKCFnHPVoOxgS1EKAMYkrLMIRgF6EoBeh CEEnIlSPkIUwAHuQHXPHSz9qs3P082EeiyQZw+hFJHQ0J4z8p6oY9lYutjwQcGnLywd5haBjAYtS Z0sYvzAXkWhhqEv56VG3ZtemAoVrP/XpFpBYRCy08Ig9pRAwrgJujmclCUkUw1WpcNFn9okXGLnK LjfGNrZnpacUsghFKQrRtwniohWNQhbDkEgwVCHuqu4tRqo6GMBaIe9696ve9HZgZabGNWRlrRX9 ztrPWuEvZPUbEmFoRSlI4QqCJ+szVrXWL3xRr4pb/OKH6ky9XtaYX7crU5pCVKf+ZtGJYrtr2pgx jSBW8TWd8AtjBpsYy1fRipX/a+Vfk7nMdSKIfKNLNOiKWstcsShYCJ3oMEM6y5S+KFSggtZteEXM UCaYPP3s6gI/2tMMPq2T4WVR0IODJ05B9rKfwhR8gNv61FYHttMvDuabAxwsIT0rVMF5crgXY25R NoVaLqF3i+jY6ra5iEL0bG4bW+AF6kAq34LmghhFKERB+cqLAhSa2ITmM695TnBC86DXPAw2MbCv zWEVgoDEKlrdiFy4h3W0i73sY58Yv2xsDnWQQx3mgHuJyQH3vP997P9A/ECkT/jCn4McaOH6CBV1 DGRQq/Snr1YzTD/61Mc+9bP+P31ohg0q2w8/9qc4BieUX61lWIIEICCBJrgfCfCXgAQYMP0sCmMO gSSk/vNvxB3+kP8sRBtxcQx9kkRTdIBkUAYxtIBTFAVOtARTZIAMiESTwhd1UET6l4EaOEhSkARS wEL75BcbeAZlUAZS4IB+dAEWIAVLtH+ENCmLRgZp1EZfVIM2GEY1iAMPsIM8mASN1E1HcQYEcgvT VwHyJwFJAH9IIAEOcARP8AThF4VSKH2GlAxoYE09kAJbQAUJZARFAAFguH5gWATnhEY9sEFiIYS0 tCjO1IZu+IZCAYNQwUofIAIdAARBkAB3gAdEQAERAIYQMARDQAR4YAceMALyI1ACiDgCJBACi/iI J1ACrKSGh2RO4XSJ3pSJ50ROmmiJPmBIyqAG/vMAEGAEm1iG9PRGmjhOrEiJjLGJlhiLnPg/bDSL rHhPhjQVOwcwuwgw+4J69BYwp3cwOjcwnvQZCYFqBqGMBcGMBOGMlcFb7KFVjjUXGOEeF2WNGKGN JXWNmNFU3RE7PMVbe1EaWlUXTjEaYFFTHbEleIIX28iOFhFxJZVe6uJYe8JT4nhSvJUZpYEkAzED 8EgddJEMlqEXpGVdEeUDZzUQjUEX8igSAuEKM4BUc8E3WhQHChYj2CEQx2IZdbCP1qVXJPllJUmS AQEAOw== ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/go.gif R0lGODlhJwAUAOYAAKPE1v////b4+ff5+szd5naQnqS2v7PJ2Pj6+5Oyw8ra5XOMnPb3+NPj7OXq 7ZytuO3z9+/y9H2bsd3p8N/p7rbDy9zi5pqrtoGcq4eisb3U4Y+sva3E0aW0v5ayx5e1xpOzxZaw voimt5u5yuPn64+tw+3x86TF1+fs73+YrNDc5env9Ku9x6a4waa/zePr8bDG03eSpOTt8rLF0tji 6N/m6Z2ywXWQobHM24qpvYKftLfQ3qzCzoWkvN3k6LrHzoShtIqeq63I15utusXX4aC2xeLq8HuX qNvh5YWkt/L1967G1LnFzerw9NDa39Hd5rDAyb7J0XSOob/T3e7099Hh6q3L3L7L0Yyswoenv5W2 y5q7zpCxxqfI2p/A067P4HqasqvM3X+gt4Oku3yctbDR4jd3fkSRpAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACH5 BAAAAAAALAAAAAAnABQAAAf/gGeCg4SFhoeIhGaLjI2Oj5CRZoJmZZaXmJmam5uTZ5WcoaKdlF+m p6ipqqurnmZhsLGys7S1ta5dubq5JyFOAwFKDbojLBEBCBNWu8xdrgDQ0dAZNQhTPFcBVQAfLQEU MFADVNLlAK5e6epeCQYBO+kbRDheGCgQ6e0BGuv9rlsAA24R8SPAFhAuOCwRsqVAAAIBHUIUKNCV losYtQBhEkDLEQsBAsjQsiCAAowlT2bM6IqLy5dccgQJcMBlDB8vuNxw0MRlkgc0YQp1haWo0aJS kAyYYaOCACNYdFwIQKNIBwErjmrF4iqL169ee6SIwiCACRUevEoYQiKAgCclOMDKzeJqjN27ePPq 3bvXlZi/gAMLHkyYsCsyiBMrXsy4cWNXYCJLnky5smXLriRp3vwokefPngMBADs= ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/wm-ijmedsci.gif R0lGODlhFAAsAYAAAP///2aZzCwAAAAAFAAsAQACr4yPqcvtD6OctNqLs968+w+G4kiW5omm6sq2 7gvH8kzX9o3n+s73/g8MCofEovGITCqXzKbzCY1uANRq9Wa9VgAYrsX7yIJT44ZYa06Uk9TtZR2B x8/S0rlNwUOsEv0W/bd3h5PVZ+Alp3a4uMeYqAiIxRen2IjweDCGmTlYR4IXuQA2GpZp6kDKmKa6 qeVXU0h5KXtqGbDpQofrydvr+wscLDxMXGx8jJysvMz8UwAAOw== ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/css/pmcstatic.css BODY.pmc-body { MARGIN: 1px } BODY.pmc-body-table { MARGIN: auto auto auto 1px } BODY.pmc-body-figure { MARGIN: auto auto auto 1px } .span-content { =09 } .front-matter-section { MARGIN-TOP: 0em; MARGIN-BOTTOM: 1.2em; WIDTH: 650px } .section-content { MARGIN-TOP: 0em; MARGIN-BOTTOM: 1.2em; WIDTH: 650px } .section-title { MARGIN-TOP: 0em; MARGIN-BOTTOM: 1.2em; WIDTH: 650px } .toc-section-title { MARGIN-TOP: 0em; MARGIN-BOTTOM: 1.2em; WIDTH: 650px } .back-matter-section { MARGIN-TOP: 0em; MARGIN-BOTTOM: 1.2em; WIDTH: 650px } .footer-section { MARGIN-TOP: 0em; MARGIN-BOTTOM: 1.2em; WIDTH: 650px } .back-matter-section { FONT-SIZE: 80% } .section-content { MARGIN-TOP: 0px; LINE-HEIGHT: 1.31em } .section-title { PADDING-BOTTOM: 0.1em; PADDING-TOP: 0.1em } .toc-section-title { PADDING-BOTTOM: 0.1em; PADDING-TOP: 0.1em } .banner-color1 { BACKGROUND-COLOR: #3c78bc } .banner-color2 { BACKGROUND-COLOR: #a0c0e0 } .banner-text { PADDING-RIGHT: 0.3em; FONT-WEIGHT: bold; FONT-SIZE: 135%; COLOR: = #ffffff; FONT-STYLE: italic; TEXT-ALIGN: right } .banner-text-sans { FONT-WEIGHT: bold; FONT-SIZE: 120%; COLOR: #ffffff; FONT-FAMILY: = sans-serif; TEXT-ALIGN: right } .banner-generic-logo-background { BACKGROUND-IMAGE: url(../pmcgifs/logo-generic.png); WIDTH: 500px; = BACKGROUND-REPEAT: no-repeat; HEIGHT: 75px; BACKGROUND-COLOR: silver } .banner-journal-publisher-over-image { MARGIN-LEFT: 84px; MARGIN-RIGHT: 20px; FONT-FAMILY: sans-serif; = TEXT-ALIGN: left } .banner-journal-name { FONT-WEIGHT: bold; FONT-SIZE: 20px; COLOR: white; PADDING-TOP: 3px; = HEIGHT: 50px } .banner-publisher-name { FONT-WEIGHT: bold; FONT-SIZE: 12px; COLOR: #0032c8 } .menu-link { FONT-WEIGHT: bold; FONT-SIZE: 13px; COLOR: #0000c0; FONT-FAMILY: = Verdana, Arial, sans-serif; TEXT-ALIGN: center; TEXT-DECORATION: none } A.menu-link:visited { FONT-WEIGHT: bold; FONT-SIZE: 13px; COLOR: #0000c0; FONT-FAMILY: = Verdana, Arial, sans-serif; TEXT-ALIGN: center; TEXT-DECORATION: none } .menu-curr-page { FONT-WEIGHT: bold; FONT-SIZE: 13px; COLOR: #ffffff; FONT-FAMILY: = Verdana, Arial, sans-serif; TEXT-ALIGN: center } A.menu-link:hover { COLOR: #ffffff; TEXT-DECORATION: none } .header-link { FONT-WEIGHT: bold; FONT-SIZE: 110%; COLOR: #0055aa; FONT-FAMILY: Arial, = sans-serif } .inpage-link { COLOR: #004080 } .sans75 { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .sans80 { FONT-SIZE: 80%; FONT-FAMILY: Arial, sans-serif } .sans80b { FONT-WEIGHT: bold; FONT-SIZE: 80%; FONT-FAMILY: Arial, sans-serif } .sans90 { FONT-SIZE: 90%; FONT-FAMILY: Arial, sans-serif } .sans90b { FONT-WEIGHT: bold; FONT-SIZE: 90%; FONT-FAMILY: Arial, sans-serif } .sans { FONT-FAMILY: Arial, sans-serif } .sans105b { FONT-WEIGHT: bold; FONT-SIZE: 105%; FONT-FAMILY: Arial, sans-serif } .sans125b { FONT-WEIGHT: bold; FONT-SIZE: 125%; FONT-FAMILY: Arial, sans-serif } .msg-error { FONT-WEIGHT: bold; BACKGROUND: yellow; COLOR: red } .msg-warning { FONT-WEIGHT: bold; BACKGROUND: yellow; COLOR: brown } .eqn-image { MARGIN: 5px } A.navlink { COLOR: #0055aa; TEXT-DECORATION: none } A.navlink:hover { COLOR: #0055aa; BACKGROUND-COLOR: #ccd8e4; TEXT-DECORATION: none } .navlink-box { FONT-WEIGHT: bold; FONT-SIZE: 80%; PADDING-BOTTOM: 2px; WIDTH: 675px; = PADDING-TOP: 2px; BORDER-BOTTOM: #cccccc 6px solid; FONT-FAMILY: tahoma, = verdana, Arial, sans-serif } .navlink-box-black { BORDER-BOTTOM: #000000 6px solid } .navlink-box-brtblue { BORDER-BOTTOM: #649afc 6px solid } .navlink-box-dkgreen { BORDER-BOTTOM: #006666 6px solid } .navlink-box-gray { BORDER-BOTTOM: #cccecc 6px solid } .navlink-box-green { BORDER-BOTTOM: #dce6e4 6px solid } .navlink-box-ltblue { BORDER-BOTTOM: #9ccefc 6px solid } .navlink-box-slateblue { BORDER-BOTTOM: #6c9acc 6px solid } .navlink-box-teal { BORDER-BOTTOM: #9ccecc 6px solid } .navlink-box-navy { BORDER-BOTTOM: #003399 6px solid } .fm-related-articles { BORDER-RIGHT: #ccd8e4 1px solid; PADDING-RIGHT: 5px; BORDER-TOP: = #ccd8e4 1px solid; PADDING-LEFT: 5px; PADDING-BOTTOM: 5px; MARGIN-LEFT: = 10px; BORDER-LEFT: #666699 1px solid; LINE-HEIGHT: 140%; MARGIN-RIGHT: = 15px; PADDING-TOP: 5px; BORDER-BOTTOM: #666699 1px solid } .nihms-highlight { FONT-WEIGHT: bold; FONT-SIZE: 0.8em; BACKGROUND: yellow; FLOAT: left; = MARGIN: 0px 0.2em 0px 0px; WIDTH: 4em; COLOR: #990000; TEXT-ALIGN: = center } .retraction-notice { FONT-WEIGHT: bold; FONT-SIZE: 1.2em; COLOR: red } .retraction-notice A { COLOR: red } TR[content-type=3D'shaded'] { BACKGROUND-COLOR: #cccccc } TD[content-type=3D'shaded'] { BACKGROUND-COLOR: #cccccc } TR[content-type=3D'shaded-medium'] { BACKGROUND-COLOR: #cccccc } TD[content-type=3D'shaded-medium'] { BACKGROUND-COLOR: #cccccc } TR[content-type=3D'shaded-light'] { BACKGROUND-COLOR: #e2e2e2 } TD[content-type=3D'shaded-light'] { BACKGROUND-COLOR: #e2e2e2 } TR[content-type=3D'shaded-dark'] { BACKGROUND-COLOR: #aaaaaa } TD[content-type=3D'shaded-dark'] { BACKGROUND-COLOR: #aaaaaa } TABLE.rendered TD { PADDING-RIGHT: 10px; PADDING-LEFT: 10px; PADDING-BOTTOM: 0.2em; = PADDING-TOP: 0.2em } TABLE.rendered TH { PADDING-RIGHT: 10px; PADDING-LEFT: 10px; PADDING-BOTTOM: 0.2em; = PADDING-TOP: 0.2em } TABLE.rendered TD { VERTICAL-ALIGN: top } TABLE.rendered TD[valign=3D'top'] { VERTICAL-ALIGN: top } TABLE.rendered TD[valign=3D'middle'] { VERTICAL-ALIGN: middle } TABLE.rendered TD[valign=3D'bottom'] { VERTICAL-ALIGN: bottom } .head1 { FONT-SIZE: 120% } .head2 { FONT-SIZE: 110% } .head3 { FONT-SIZE: 105% } .head4 { FONT-SIZE: 99% } .head5 { FONT-SIZE: 90% } .acknowledgment-journal-title { FONT-STYLE: italic } DIV.exception-box { BORDER-RIGHT: silver 1px dashed; PADDING-RIGHT: 0.3em; BORDER-TOP: = silver 1px dashed; PADDING-LEFT: 0.3em; FONT-SIZE: 0.87em; = MARGIN-BOTTOM: 1.31em; PADDING-BOTTOM: 0.3em; BORDER-LEFT: silver 1px = dashed; PADDING-TOP: 0.3em; BORDER-BOTTOM: silver 1px dashed } DIV.exception-box .front-matter-section { FONT-SIZE: 1.14em } DIV.p { MARGIN-TOP: 1.31em; MARGIN-BOTTOM: 1.31em } DIV.sec { MARGIN-BOTTOM: 1.31em } SUP { FONT-SIZE: 0.8em; LINE-HEIGHT: 0.8em; WHITE-SPACE: nowrap } SUB { FONT-SIZE: 0.8em; LINE-HEIGHT: 0.8em; WHITE-SPACE: nowrap } .footnote-char { MARGIN: 0px 0.1em; WIDTH: 1em; HEIGHT: 1em } .footnote-char-irp { MARGIN: 0px 0.1em; WIDTH: 1em; HEIGHT: 1em } .footnote-char-ec { MARGIN: 0px 0.1em; WIDTH: 1em; HEIGHT: 1em } .footnote-char-irp { WIDTH: 1.5em; HEIGHT: 1.1em } .tocentry .footnote-char-irp { WIDTH: 1.5em; HEIGHT: 1.1em } .footnote-char-ec { WIDTH: 1.5em; HEIGHT: 1.1em } .tocentry .footnote-char-ec { WIDTH: 1.5em; HEIGHT: 1.3em } ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/css/pmcbase1.css BODY { BACKGROUND-COLOR: #f8f8f8 } .small-caps { FONT-SIZE: 80%; FONT-VARIANT: small-caps } .monospace { FONT-FAMILY: monospace } .pmctop-bg { BACKGROUND-COLOR: #fffeee } A.pmctop { FONT-SIZE: 12px; COLOR: #004080; FONT-FAMILY: Arial, sans-serif; = TEXT-DECORATION: none } .pmc-body A:active { COLOR: #0080ff; TEXT-DECORATION: underline } .pmc-body A:hover { COLOR: #0080ff; TEXT-DECORATION: underline } .pmc-body-table A:active { COLOR: #0080ff; TEXT-DECORATION: underline } .pmc-body-table A:hover { COLOR: #0080ff; TEXT-DECORATION: underline } .pmc-body-figure A:active { COLOR: #0080ff; TEXT-DECORATION: underline } .pmc-body-figure A:hover { COLOR: #0080ff; TEXT-DECORATION: underline } .pmc-body A:hover { COLOR: #0080ff; TEXT-DECORATION: underline } .pmc-body A:hover { BACKGROUND-COLOR: #ccd8e4 } .pmc-body-table A:hover { BACKGROUND-COLOR: #ccd8e4 } .pmc-body-figure A:hover { BACKGROUND-COLOR: #ccd8e4 } HR { COLOR: #0072a8 } .base-highlight1 { BACKGROUND-COLOR: #ebebeb } .base-highlight2 { BACKGROUND-COLOR: #cccccc } .controls { FONT-WEIGHT: bold; FONT-SIZE: 75%; COLOR: #000000; FONT-FAMILY: = Verdana, Arial, sans-serif; TEXT-DECORATION: none } .formtext { FONT-SIZE: 80%; FONT-FAMILY: Arial, sans-serif } .link { COLOR: #0055aa; TEXT-DECORATION: none } .footer-link { FONT-SIZE: 80%; FONT-FAMILY: Arial, sans-serif; TEXT-ALIGN: center } .side-head { FONT-WEIGHT: bold; FONT-SIZE: 90%; FONT-FAMILY: Arial, sans-serif } .side-subhead { MARGIN-TOP: 10px; FONT-WEIGHT: bold; FONT-SIZE: 75%; FONT-FAMILY: = Arial, sans-serif } .side-item { FONT-SIZE: 75%; PADDING-BOTTOM: 2px; MARGIN: 2px 1px 2px 4px; = BORDER-BOTTOM: #c0c0c0 1px solid; FONT-FAMILY: Arial, sans-serif } .side-curr-item { FONT-SIZE: 75%; PADDING-BOTTOM: 2px; MARGIN: 2px 1px 2px 4px; = BORDER-BOTTOM: #c0c0c0 1px solid; FONT-FAMILY: Arial, sans-serif } .side-item A { COLOR: #0055aa; TEXT-DECORATION: none } .side-curr-item { COLOR: #808080 } .toc-header-vid { FONT-WEIGHT: bold; FONT-SIZE: 120%; MARGIN-BOTTOM: 1.1em; LINE-HEIGHT: = 1.1em; FONT-FAMILY: Arial, sans-serif } .more-iss-text { MARGIN-TOP: 1.5em; FONT-WEIGHT: bold; FONT-FAMILY: Arial, sans-serif } .more-iss-link { COLOR: #0055aa; TEXT-DECORATION: none } .arc-issue { FONT-SIZE: 80%; COLOR: #004080; FONT-FAMILY: Arial, sans-serif; = TEXT-ALIGN: center; TEXT-DECORATION: none } .toc-entry { LINE-HEIGHT: 1.12em } .toc-comment { FONT-SIZE: 70%; FONT-FAMILY: Arial, sans-serif } .toc-title { FONT-WEIGHT: bold; FONT-SIZE: 80%; FONT-FAMILY: Arial, sans-serif } .toc-author { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .toc-cit-jour { FONT-SIZE: 75%; COLOR: #666666; FONT-STYLE: italic; FONT-FAMILY: Arial, = sans-serif } .toc-cit-vol { FONT-SIZE: 75%; COLOR: #666666; FONT-FAMILY: Arial, sans-serif } .toc-cit-page { FONT-WEIGHT: bold; FONT-SIZE: 75%; COLOR: #666666; FONT-FAMILY: Arial, = sans-serif } .toc-cit-date { FONT-SIZE: 75%; COLOR: #666666; FONT-FAMILY: Arial, sans-serif; = WHITE-SPACE: nowrap } .toc-pmcid { FONT-SIZE: 75%; COLOR: #666666; FONT-FAMILY: Arial, sans-serif; = WHITE-SPACE: nowrap } .toc-link { FONT-SIZE: 75%; COLOR: #004080; FONT-FAMILY: Arial, sans-serif; = TEXT-DECORATION: none } .toc-divider { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif; TEXT-DECORATION: none } .toc-corrected-citation { MARGIN-LEFT: 1em } .toc-corrected-prefix { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .toc-corrected-1st-author-etal { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .toc-corrected-citation-title { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .toc-corrected-prefix { FONT-WEIGHT: 600 } .toc-corrected-citation-info { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .toc-corrected-citation-info .citation-abbreviation { FONT-STYLE: italic } .toc-entry-abstract-toc { PADDING-RIGHT: 2em; PADDING-LEFT: 2em; FONT-SIZE: 75%; PADDING-BOTTOM: = 0px; COLOR: #333; PADDING-TOP: 0px; FONT-FAMILY: Arial, san-serif } .cited-article-fm { BORDER-RIGHT: 1px solid; PADDING-RIGHT: 8px; BORDER-TOP: 1px solid; = PADDING-LEFT: 8px; MARGIN-LEFT: 0px; BORDER-LEFT: 1px solid; = BORDER-BOTTOM: 1px solid; BACKGROUND-COLOR: #ebebeb } .citing-article-fm { PADDING-RIGHT: 8px; PADDING-LEFT: 8px; MARGIN-LEFT: 0px } .sidefm-pmchead { FONT-WEIGHT: bold; FONT-SIZE: 85%; COLOR: #0055aa; FONT-FAMILY: = Verdana, Arial, sans-serif; TEXT-DECORATION: none } .sidefm-pmhead { FONT-WEIGHT: bold; FONT-SIZE: 85%; COLOR: #0055aa; FONT-FAMILY: = Verdana, Arial, sans-serif; TEXT-DECORATION: none } .sidefm-pmsubhead { MARGIN-TOP: 10px; FONT-WEIGHT: bold; FONT-SIZE: 75%; COLOR: #000000; = FONT-FAMILY: Arial, sans-serif } .sidefm-pmclink { FONT-SIZE: 75%; COLOR: #004080; FONT-FAMILY: Arial, sans-serif; = TEXT-DECORATION: none } .sidefm-pmart { FONT-SIZE: 75%; COLOR: #004080; FONT-FAMILY: Arial, sans-serif; = TEXT-DECORATION: none } .side-section { FONT-SIZE: 75%; COLOR: #004080; FONT-FAMILY: Arial, sans-serif; = TEXT-DECORATION: none } .side-caption { FONT-SIZE: 75%; COLOR: #004080; FONT-FAMILY: Arial, sans-serif; = TEXT-DECORATION: none } .figure-table-caption-in-article { FONT-SIZE: 75%; COLOR: #004080; FONT-FAMILY: Arial, sans-serif; = TEXT-DECORATION: none } .figure-table-caption-in-article { COLOR: #000000; LINE-HEIGHT: 1.5em } .sidefm-pmclink-item { PADDING-LEFT: 10px } .sidefm-pmclink-item A { DISPLAY: block; PADDING-LEFT: 5px; PADDING-BOTTOM: 2px; LINE-HEIGHT: = 1.5em; BORDER-BOTTOM: #c0c0c0 1px dotted; TEXT-DECORATION: none } .sidefm-pmccurrent-item A { DISPLAY: block; PADDING-LEFT: 5px; PADDING-BOTTOM: 2px; LINE-HEIGHT: = 1.5em; BORDER-BOTTOM: #c0c0c0 1px dotted; TEXT-DECORATION: none } .sidefm-pmclink-item A:hover { DISPLAY: block; PADDING-LEFT: 5px; PADDING-BOTTOM: 2px; LINE-HEIGHT: = 1.5em; BORDER-BOTTOM: #c0c0c0 1px dotted; TEXT-DECORATION: none } .sidefm-pmccurrent-item A:hover { DISPLAY: block; PADDING-LEFT: 5px; PADDING-BOTTOM: 2px; LINE-HEIGHT: = 1.5em; BORDER-BOTTOM: #c0c0c0 1px dotted; TEXT-DECORATION: none } .sidefm-pmclink-item A { COLOR: #004080 } .sidefm-pmclink-item A:hover { BACKGROUND-COLOR: #b8c8d8 } .sidefm-pmccurrent-item A:hover { BACKGROUND-COLOR: #b8c8d8 } .sidefm-pmccurrent-item A { CURSOR: default; COLOR: #808080 } .sidefm-pmccurrent-item A:hover { CURSOR: default; COLOR: #808080 } .sidefm-pmccurrent-item A:hover { BACKGROUND-COLOR: #dcdcdc } .side-section-curr { FONT-SIZE: 75%; COLOR: #808080; FONT-FAMILY: Arial, sans-serif; = TEXT-DECORATION: none } .sidebar-cell .sidefm-supplink { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .sidebar-cell .side-supplink { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } A.sidefm-supplink { COLOR: #b55a00; TEXT-DECORATION: none } A.side-supplink { COLOR: #b55a00; TEXT-DECORATION: none } .side-section-group { PADDING-RIGHT: 3px; BORDER-TOP: #0077aa 1px solid; PADDING-LEFT: 3px; = LINE-HEIGHT: 100%; TEXT-DECORATION: none } .head-separate { MARGIN: 1.2em 0px } .links-box { BORDER-RIGHT: #ccd8e4 1px solid; PADDING-RIGHT: 5px; BORDER-TOP: = #ccd8e4 1px solid; PADDING-LEFT: 5px; PADDING-BOTTOM: 5px; MARGIN: 1.5em = 15px 1.5em 10px; BORDER-LEFT: #666699 1px solid; PADDING-TOP: 5px; = BORDER-BOTTOM: #666699 1px solid } :unknown { BORDER-RIGHT: #336699 1px dotted; BORDER-TOP: #336699 1px dotted; = BORDER-LEFT: #336699 1px dotted; BORDER-BOTTOM: #336699 1px dotted } .main-table-content { MARGIN-LEFT: 9px } .main-figure-content { MARGIN-LEFT: 9px } .fm-copyright { MARGIN-TOP: 16px; MARGIN-BOTTOM: 16px } .fm-author { MARGIN-TOP: 16px; MARGIN-BOTTOM: 16px } .fm-affl { MARGIN-TOP: 16px; FONT-WEIGHT: normal; MARGIN-BOTTOM: 12px } .fm-footnote { MARGIN-TOP: 12px; MARGIN-BOTTOM: 12px } .fm-pubdate { MARGIN-TOP: 12px; MARGIN-BOTTOM: 12px } .fm-citation { MARGIN-TOP: 0px } .fm-citation-ids { PADDING-LEFT: 1em; FONT-SIZE: 85%; FONT-FAMILY: Arial,sans-serif; = WHITE-SPACE: nowrap; TEXT-ALIGN: right } .fm-citation-ids-label { COLOR: #666 } .fm-citation-pmcid { =09 } .fm-citation-manuscriptid { =09 } .fm-copyright { MARGIN-TOP: 6px } .links-box .fm-footnote { MARGIN: 0px } .tocentry { MARGIN-TOP: 1.12em; MARGIN-BOTTOM: 1.12em } .toc-entry-alt-lang { MARGIN-TOP: 1.12em; MARGIN-BOTTOM: 1.12em } .toc-entry-alt-lang { MARGIN-LEFT: 2.5em } .toc-entry-alt-lang-msg { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .portal-tocentry { MARGIN-TOP: 1.6ex; MARGIN-BOTTOM: 2ex; MARGIN-RIGHT: 1em } .button-elsevierwt { BORDER-TOP-WIDTH: 0px; BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: = 0px; BORDER-RIGHT-WIDTH: 0px } .elsevierwt-sponsored-label { FONT-WEIGHT: 600; COLOR: #f8f8f8 } .banner-journal-publisher-over-image-elsevierwt { MARGIN-LEFT: 20px; OVERFLOW: hidden; COLOR: #9a7947; LINE-HEIGHT: = 1.5em; MARGIN-RIGHT: 145px; FONT-FAMILY: Georgia, "Times New Roman", = Times, serif; POSITION: relative; TOP: -30px; HEIGHT: 75px } .banner-journal-name-elsevierwt { FONT-WEIGHT: 600; FONT-SIZE: 1.2em; MARGIN-LEFT: 1em; COLOR: #954a4a } A.elsevierwt-button-link { LEFT: 360px; POSITION: relative; TOP: 40px } A.elsevierwt-button-link:hover { BACKGROUND-COLOR: #f1e8ce } .fm-elsevierwt-disclaimer { MARGIN-TOP: 12px; FONT-SIZE: 0.68em; MARGIN-BOTTOM: 12px; FONT-FAMILY: = Arial, sans-serif } .ref-cit-blk { MARGIN-TOP: 1.4em; LINE-HEIGHT: 1.4em } .back-ref-list-1st-line-shifted LI { MARGIN-TOP: 1.4em; LINE-HEIGHT: 1.4em } .back-ref-list LI { MARGIN-TOP: 1.4em; LINE-HEIGHT: 1.4em } DIV.ref-label { BORDER-RIGHT: #f8f8f8 1px solid; BORDER-TOP: #f8f8f8 1px solid; FLOAT: = left; BORDER-LEFT: #f8f8f8 1px solid; WIDTH: 45px; BORDER-BOTTOM: = #f8f8f8 1px solid; TEXT-ALIGN: right } DIV.ref-cit { MARGIN-LEFT: 55px } SPAN.ref-label { FONT-STYLE: italic } SPAN.ref-cit { =09 } .back-ref-list-1st-line-shifted LI { PADDING-LEFT: 1.5em; MARGIN-LEFT: 2em; TEXT-INDENT: -1.5em; = LIST-STYLE-TYPE: none } .array-table { MARGIN-TOP: 1em; MARGIN-BOTTOM: 1em; WIDTH: 100%; LINE-HEIGHT: 1.31em; = BACKGROUND-COLOR: #f4f4f4 } .array-table-inline { MARGIN-TOP: 1em; MARGIN-BOTTOM: 1em; WIDTH: 100%; LINE-HEIGHT: 1.31em; = BACKGROUND-COLOR: #f4f4f4 } .array-table TD { PADDING-RIGHT: 0.5em; PADDING-LEFT: 0.5em; PADDING-BOTTOM: 0em; = PADDING-TOP: 0em } .array-table-inline { DISPLAY: inline } .list-item-w-pw { BORDER-RIGHT: #f8f8f8 1px solid; BORDER-TOP: #f8f8f8 1px solid; = BORDER-LEFT: #f8f8f8 1px solid; BORDER-BOTTOM: #f8f8f8 1px solid } .list-item-w-pw-prefix-word { DISPLAY: inline-block; POSITION: relative; TEXT-ALIGN: right } .list-item-w-pw-content { POSITION: relative; TOP: -1.35em } .list-item-p-question { FONT-WEIGHT: bold } SPAN.underline { BORDER-BOTTOM: black 1px solid } SPAN.double-underline { BORDER-BOTTOM: black 3px double } SPAN.bold-double-underline { BORDER-BOTTOM: black 3px double } .verse-group { FONT-SIZE: 1.12em; MARGIN: 1.31em 2em; LINE-HEIGHT: 1.16em; = FONT-FAMILY: "Monotype Corsiva", "Apple Chancery", "URW Chancery L", = cursive } .internal-control { PADDING-RIGHT: 0.5em; PADDING-LEFT: 0.5em; FONT-WEIGHT: bold; = PADDING-BOTTOM: 0.5em; MARGIN: 1.5em auto; WIDTH: 95%; PADDING-TOP: = 0.5em; BACKGROUND-COLOR: #f0f0f0 } .sidebar-menu-square-image-holder { PADDING-RIGHT: 0.35em; VERTICAL-ALIGN: middle; _padding-top: 0.35em } DIV.figure-role { MARGIN: 1em 0px } DIV.signature { MARGIN: 1.8em 0px; FONT-FAMILY: "Monotype Corsiva", "Apple Chancery", = "URW Chancery L", cursive } DIV.simple-list-item-w-label { FLOAT: left; TEXT-INDENT: -2em } .selective-deposit-msg { BORDER-RIGHT: #f4f4f4 0.5em solid; BORDER-TOP: #f4f4f4 0.5em solid; = FONT-SIZE: 80%; BORDER-LEFT: #f4f4f4 0.5em solid; BORDER-BOTTOM: #f4f4f4 = 0.5em solid; FONT-FAMILY: Arial,sans-serif; BACKGROUND-COLOR: #f4f4f4 } .fm-title { MARGIN-TOP: 16px } .fm-trans-title { MARGIN-TOP: 16px } ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/css/pmcbars-slateblue.css .doc-group1 { FONT-WEIGHT: bold; FONT-SIZE: 110%; COLOR: white; FONT-FAMILY: Verdana, = sans-serif; BACKGROUND-COLOR: #0072a8 } .doc-group2 { FONT-WEIGHT: bold; COLOR: #004080; FONT-FAMILY: Arial, sans-serif; = BACKGROUND-COLOR: #cccccc; TEXT-ALIGN: center } .doc-group3 { FONT-WEIGHT: bold; COLOR: #000000; FONT-FAMILY: Arial, sans-serif; = BACKGROUND-COLOR: #cccccc; TEXT-ALIGN: center } .doc-group4 { =09 } .toc-supp-link { FONT-SIZE: 75%; COLOR: #e64a00; FONT-FAMILY: Arial, sans-serif; = TEXT-DECORATION: none } .toc-highlight1 { BACKGROUND-COLOR: #ffffd0 } .toc-highlight2 { BACKGROUND-COLOR: #ace4ff } .head1 { BORDER-RIGHT: #0072a8 1pt solid; BORDER-TOP: #0072a8 1pt solid; = FONT-WEIGHT: bold; FONT-SIZE: 110%; BORDER-LEFT: #0072a8 1pt solid; = COLOR: white; BORDER-BOTTOM: #0072a8 1pt solid; FONT-FAMILY: Verdana, = sans-serif; BACKGROUND-COLOR: #0072a8; TEXT-ALIGN: center } .head1A { FONT-WEIGHT: bold; COLOR: #004080; FONT-FAMILY: Arial, sans-serif; = BACKGROUND-COLOR: #cccccc } .append-head1 { FONT-WEIGHT: bold; FONT-FAMILY: Arial, sans-serif; TEXT-ALIGN: center } .colorbar-link { COLOR: #ffffff } .head1 A:link { COLOR: white } .head1 A:visited { COLOR: white } .head1A A:link { COLOR: white } .head1A A:visited { COLOR: white } ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/css/pmcbody7.css .fm-vol-iss-date { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif; TEXT-ALIGN: left } .fm-citation { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif; TEXT-ALIGN: left } .fm-citation-ids { FONT-SIZE: 75% } .fm-citation .fm-vol-iss-date { FONT-SIZE: 100% } .pubnote { FONT-WEIGHT: bold; FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .pubnote-hilite { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif; BACKGROUND-COLOR: = #ebebeb } .fm-dochead { FONT-WEIGHT: bold; FONT-SIZE: 80%; FONT-FAMILY: Arial, sans-serif } .fm-doctopic { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .fm-docsubject { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .fm-ser-title { FONT-WEIGHT: bold; FONT-SIZE: 80%; FONT-FAMILY: Arial, sans-serif } .fm-supp-title { FONT-WEIGHT: bold; FONT-SIZE: 80%; FONT-FAMILY: Arial, sans-serif } .fm-title { FONT-WEIGHT: bold; FONT-SIZE: 125%; FONT-FAMILY: Arial, sans-serif } .fm-subtitle { FONT-WEIGHT: bold; FONT-FAMILY: Arial, sans-serif } .fm-trans-title { FONT-SIZE: 120%; FONT-FAMILY: Arial, sans-serif } .fm-trans-subtitle { FONT-SIZE: 105%; FONT-FAMILY: Arial, sans-serif } .fm-author { FONT-SIZE: 110%; FONT-FAMILY: Arial, sans-serif } .fm-affl { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .fm-pubdate { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .fm-editor { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .fm-footnote { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .fm-author .fm-footnote { FONT-SIZE: 68.5% } .fm-author .fm-affl { FONT-SIZE: 68.5% } .fm-author .fm-footnote .fm-affl { FONT-SIZE: 100%; FONT-FAMILY: Arial, sans-serif } .fm-editor .fm-footnote .fm-affl { FONT-SIZE: 100%; FONT-FAMILY: Arial, sans-serif } .fm-editor .fm-footnote { FONT-SIZE: 100%; FONT-FAMILY: Arial, sans-serif } .fm-role { FONT-STYLE: italic; FONT-FAMILY: Arial, sans-serif } .fm-copyright { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .pmcnote { FONT-SIZE: 85%; FONT-FAMILY: Arial, sans-serif } .abs-head2 { =09 } .abs-head2 { FONT-WEIGHT: bold; FONT-FAMILY: Arial, sans-serif } .kwd-label { FONT-WEIGHT: bold; FONT-FAMILY: Arial, sans-serif } .head2 { FONT-WEIGHT: bold; FONT-STYLE: italic; FONT-FAMILY: Arial, sans-serif } .head3 { FONT-WEIGHT: bold; FONT-FAMILY: Arial, sans-serif } .head4 { FONT-STYLE: italic; FONT-FAMILY: Arial, sans-serif } .head5 { =09 } .kwd-text { FONT-SIZE: 85% } .eqn-image { TEXT-ALIGN: center } .eqn-id { FONT-WEIGHT: bold; TEXT-ALIGN: right } .box { BORDER-RIGHT: #60cfff 1px solid; BORDER-TOP: #60cfff 1px solid; = OVERFLOW: auto; BORDER-LEFT: #60cfff 1px solid; BORDER-BOTTOM: #60cfff = 1px solid; BACKGROUND-COLOR: #e1e1e1 } .boxhead1 { FONT-WEIGHT: bold; FONT-SIZE: 105%; FONT-FAMILY: Arial, sans-serif } .boxhead2 { FONT-WEIGHT: bold } .fig-table-link { COLOR: #0050a0; TEXT-DECORATION: none } A.cite-reflink { COLOR: #0050a0; TEXT-DECORATION: none } A.int-reflink { COLOR: #0050a0 } A.ext-reflink { COLOR: #0050a0 } .figwind-cite { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .figwind-copyrt { FONT-SIZE: 75%; FONT-FAMILY: Arial, sans-serif } .product-source { FONT-STYLE: italic } .signature-group { FONT-WEIGHT: bold; MARGIN-LEFT: 2em; FONT-STYLE: italic } TR[content-type=3D'shaded'] { BACKGROUND-COLOR: #cccccc } TD[content-type=3D'shaded'] { BACKGROUND-COLOR: #cccccc } TR[content-type=3D'shaded-medium'] { BACKGROUND-COLOR: #cccccc } TD[content-type=3D'shaded-medium'] { BACKGROUND-COLOR: #cccccc } TR[content-type=3D'shaded-light'] { BACKGROUND-COLOR: #e2e2e2 } TD[content-type=3D'shaded-light'] { BACKGROUND-COLOR: #e2e2e2 } TR[content-type=3D'shaded-dark'] { BACKGROUND-COLOR: #aaaaaa } TD[content-type=3D'shaded-dark'] { BACKGROUND-COLOR: #aaaaaa } ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: 7bit Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/css/pmcrefs5.css .ref-id { } .ref-title { } .ref-author { } .ref-journal { } .ref-pubdate { } .ref-vol { } .ref-iss { } .ref-page { } .ref-edition { } .ref-editor { } .ref-pubname { } .ref-publoc { } .ref-extlink { COLOR: #0050a0 } ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.ncbi.nlm.nih.gov/corehtml/jsutils/css/tileshop_pmc.1/tileshop_pmc.1.css .viewport { -moz-user-select: none; -khtml-user-select: none; user-select: none } .viewport-static-image { -moz-user-select: none; -khtml-user-select: none; user-select: none } .panorama { -moz-user-select: none; -khtml-user-select: none; user-select: none } .scale-pmc { -moz-user-select: none; -khtml-user-select: none; user-select: none } .viewport { FLOAT: left } .viewport-static-image { FLOAT: left } .viewport { BACKGROUND-IMAGE: url(../../img/tileshop_pmc.1/loading_bg.gif); = OVERFLOW: hidden } .viewport .dnd { BACKGROUND-IMAGE: url(../../img/tileshop_pmc.1/loading_bg.gif) } .dnd { MARGIN-LEFT: auto; CURSOR: = url(http://www.ncbi.nlm.nih.gov/corehtml/jsutils/cur/grab.cur), move; = MARGIN-RIGHT: auto } .moving { CURSOR: = url(http://www.ncbi.nlm.nih.gov/corehtml/jsutils/cur/grabbing.cur), move } .viewport-static-image { BACKGROUND-IMAGE: none; OVERFLOW: hidden; BACKGROUND-COLOR: #ccc } .viewport-static-image IMG { CURSOR: = url(http://www.ncbi.nlm.nih.gov/corehtml/jsutils/cur/zoomin.cur), auto } .tileshop { FLOAT: left; CURSOR: = url(http://www.ncbi.nlm.nih.gov/corehtml/jsutils/cur/zoomin.cur), auto; = BACKGROUND-COLOR: #fff } .nodrag { CURSOR: default } .static { BACKGROUND-IMAGE: none; CURSOR: default; BACKGROUND-COLOR: #ccc } .static IMG { BACKGROUND-IMAGE: none; CURSOR: default; BACKGROUND-COLOR: #ccc } .half-static { BACKGROUND-IMAGE: none; BACKGROUND-COLOR: #ccc } .half-static IMG { BACKGROUND-IMAGE: none; BACKGROUND-COLOR: #ccc } .tile-fill { BACKGROUND-COLOR: #f0f } .panorama { BORDER-RIGHT: #f0ffff 3px solid; BORDER-TOP: black 1px solid; = BORDER-LEFT: black 1px solid; BACKGROUND-COLOR: #ecf0f4; = BORDER-BOTTOM-STYLE: none } .panorama DIV { OVERFLOW: hidden } .panorama IMG { CURSOR: pointer } .pan-switcher { BORDER-RIGHT: #000 1px solid; BORDER-TOP: #000 1px solid; = BACKGROUND-IMAGE: url(../../img/tileshop_pmc.1/pan_close.gif); = BORDER-LEFT: #000 1px solid; WIDTH: 10px; CURSOR: pointer; = BORDER-BOTTOM: #000 1px solid; BACKGROUND-REPEAT: no-repeat; HEIGHT: = 10px; BACKGROUND-COLOR: #fff; _background-color: transparent; _border: = none } .pan-switcher-close { BACKGROUND-IMAGE: url(../../img/tileshop_pmc.1/pan_open.gif) } .pan { BORDER-RIGHT: #000 2px dotted; BORDER-TOP: #000 2px dotted; FONT-SIZE: = 1px; FILTER: alpha(opacity=3D70); BORDER-LEFT: #000 2px dotted; CURSOR: = move; BORDER-BOTTOM: #000 2px dotted; BACKGROUND-COLOR: #dce0e4; = opacity: 0.7 } DIV.panel { BORDER-RIGHT: gray 1px solid; PADDING-RIGHT: 0px; BORDER-TOP: gray 1px = solid; PADDING-LEFT: 0px; FLOAT: left; PADDING-BOTTOM: 0px; MARGIN: 0px; = BORDER-LEFT: gray 1px solid; PADDING-TOP: 0px; BORDER-BOTTOM: gray 1px = solid; BACKGROUND-COLOR: #ecf0f4 } DIV.panel P { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; MIN-HEIGHT: 21px; FLOAT: left; = PADDING-BOTTOM: 0.2em; MARGIN: 0px; WIDTH: 100%; PADDING-TOP: 0.1em; = BACKGROUND-COLOR: #ecf0f4; TEXT-ALIGN: center } DIV.panel P SPAN { PADDING-LEFT: 25px; FLOAT: left; MARGIN: 0px; WIDTH: 85% } DIV.panel P A { DISPLAY: none; MIN-HEIGHT: 21px; TEXT-DECORATION: none } DIV.panel P A.active { BACKGROUND-POSITION: 13px 0px; DISPLAY: block; FLOAT: right; = BACKGROUND-IMAGE: url(../../img/tileshop_pmc.1/toolbar.png); MARGIN: 0px = 9px 0px 0px; WIDTH: 36px; BACKGROUND-REPEAT: no-repeat; HEIGHT: 21px; = _background-image: url(../../img/tileshop_pmc.1/toolbar.gif); = _margin-right: 5px } DIV.panel P A.active:hover { BACKGROUND-POSITION: -67px 0px; BACKGROUND-REPEAT: no-repeat; = BACKGROUND-COLOR: #ecf0f4; TEXT-DECORATION: none } DIV.panel DL { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } DIV.panel DD { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } DIV.panel DT { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } DIV.panel DT IMG { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } DIV.panel DL { FLOAT: left; WIDTH: 100% } DIV.panel DL DD { FLOAT: right } DIV.panel DL DT { FLOAT: left; BACKGROUND-IMAGE: = url(../../img/tileshop_pmc.1/loading_bg.gif) } .scale-pmc { MARGIN: auto; WIDTH: 32px; PADDING-TOP: 0em } .scale-pmc A { PADDING-RIGHT: 1px; DISPLAY: block; PADDING-LEFT: 1px; FONT-SIZE: 3px; = BACKGROUND-IMAGE: url(../../img/tileshop_pmc.1/toolbar.png); = PADDING-BOTTOM: 1px; MARGIN: 0px; PADDING-TOP: 1px; BACKGROUND-REPEAT: = no-repeat; HEIGHT: 16px; TEXT-DECORATION: none; _background-image: = url(../../img/tileshop_pmc.1/toolbar.gif) } .scale-pmc A:hover { BACKGROUND-REPEAT: no-repeat; BACKGROUND-COLOR: transparent; = TEXT-DECORATION: none } .scale-pmc A.scale-up { MARGIN: 2px auto; WIDTH: 22px; HEIGHT: 22px } .scale-pmc A.scale-up-disabled { MARGIN: 2px auto; WIDTH: 22px; HEIGHT: 22px } .scale-pmc A.scale-down-disabled { MARGIN: 2px auto; WIDTH: 22px; HEIGHT: 22px } .scale-pmc A.scale-down { MARGIN: 2px auto; WIDTH: 22px; HEIGHT: 22px } .scale-pmc A.scale-up { BACKGROUND-POSITION: 4px -26px } .scale-pmc A.scale-up:hover { BACKGROUND-POSITION: -76px -26px } .scale-pmc A.scale-up-disabled { BACKGROUND-POSITION: -36px -26px; CURSOR: default } .scale-pmc A.scale-down { BACKGROUND-POSITION: 4px -226px } .scale-pmc A.scale-down:hover { BACKGROUND-POSITION: -76px -226px } .scale-pmc A.scale-down-disabled { BACKGROUND-POSITION: -36px -226px; CURSOR: default } .scale-pmc A.scale-1 { BACKGROUND-POSITION: 3px -57px } .scale-pmc A.scale-1:hover { BACKGROUND-POSITION: -77px -57px } .scale-pmc A.selected-1 { BACKGROUND-POSITION: -37px -57px; CURSOR: default } .scale-pmc A.selected-1:hover { BACKGROUND-POSITION: -37px -57px; CURSOR: default } .scale-pmc A.scale-2 { BACKGROUND-POSITION: 3px -77px } .scale-pmc A.scale-2:hover { BACKGROUND-POSITION: -77px -77px } .scale-pmc A.selected-2 { BACKGROUND-POSITION: -37px -77px; CURSOR: default } .scale-pmc A.selected-2:hover { BACKGROUND-POSITION: -37px -77px; CURSOR: default } .scale-pmc A.scale-3 { BACKGROUND-POSITION: 3px -97px } .scale-pmc A.scale-3:hover { BACKGROUND-POSITION: -77px -97px } .scale-pmc A.selected-3 { BACKGROUND-POSITION: -37px -97px; CURSOR: default } .scale-pmc A.selected-3:hover { BACKGROUND-POSITION: -37px -97px; CURSOR: default } .scale-pmc A.scale-4 { BACKGROUND-POSITION: 3px -117px } .scale-pmc A.scale-4:hover { BACKGROUND-POSITION: -77px -117px } .scale-pmc A.selected-4 { BACKGROUND-POSITION: -37px -117px; CURSOR: default } .scale-pmc A.selected-4:hover { BACKGROUND-POSITION: -37px -117px; CURSOR: default } .scale-pmc A.scale-5 { BACKGROUND-POSITION: 3px -137px } .scale-pmc A.scale-5:hover { BACKGROUND-POSITION: -77px -137px } .scale-pmc A.selected-5 { BACKGROUND-POSITION: -37px -137px; CURSOR: default } .scale-pmc A.selected-5:hover { BACKGROUND-POSITION: -37px -137px; CURSOR: default } .scale-pmc A.scale-6 { BACKGROUND-POSITION: 3px -157px } .scale-pmc A.scale-6:hover { BACKGROUND-POSITION: -77px -157px } .scale-pmc A.selected-6 { BACKGROUND-POSITION: -37px -157px; CURSOR: default } .scale-pmc A.selected-6:hover { BACKGROUND-POSITION: -37px -157px; CURSOR: default } .scale-pmc A.scale-7 { BACKGROUND-POSITION: 3px -177px } .scale-pmc A.scale-7:hover { BACKGROUND-POSITION: -77px -177px } .scale-pmc A.selected-7 { BACKGROUND-POSITION: -37px -177px; CURSOR: default } .scale-pmc A.selected-7:hover { BACKGROUND-POSITION: -37px -177px; CURSOR: default } .scale-pmc A.scale-8 { BACKGROUND-POSITION: 3px -207px } .scale-pmc A.scale-8:hover { BACKGROUND-POSITION: -77px -207px } .scale-pmc A.selected-8 { BACKGROUND-POSITION: -37px -207px; CURSOR: default } .scale-pmc A.selected-8:hover { BACKGROUND-POSITION: -37px -207px; CURSOR: default } ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/js/common.js // Called from many places to handle links.=0A= // Params:=0A= // link: URL. 'this' to reuse same window, else ""=0A= // windowname: Reference name for window=0A= // additional: Attributes for window.open, from:=0A= // width, height, resizable, scrollbars, toolbar, location, = directories,=0A= // status, menubar, copyhistory.=0A= // Notes: Book version always provides menubar, toolbar, etc.=0A= //=0A= function startTargetBook(link,windowname,width,height,additional) =0A= {=0A= if(! window.focus)=0A= return;=0A= var sizestring =3D ",width=3D" + width + ",height=3D" + height;=0A= var opt =3D = "menubar=3Dyes,toolbar=3Dyes,status=3Dyes,scrollbars,resizable,dependent=3D= yes";=0A= var allOptions =3D opt + sizestring;=0A= if (additional) { allOptions =3D allOptions + additional; }=0A= //alert("In startTargetBook, additional: " + additional);=0A= =0A= w =3D window.open("",windowname, allOptions);=0A= w.focus();=0A= link.target=3Dwindowname;=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function startTarget(link,windowname,width,height) =0A= {=0A= if(! window.focus)=0A= return;=0A= var sizestring =3D ",width=3D" + width + ",height=3D" + height;=0A= w =3D = window.open("",windowname,"scrollbars,resizable,dependent=3Dyes" + = sizestring);=0A= w.focus();=0A= link.target=3Dwindowname;=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function focuswin(windowname) =0A= {=0A= w =3D = window.open("",windowname,"menubar=3Dyes,scrollbars=3Dyes,toolbar=3Dyes,l= ocation=3Dyes,status=3Dyes,directories=3Dyes,resizable=3Dyes");=0A= w.focus();=0A= return true;=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function reverseString (inStr)=0A= {=0A= var outStr =3D ''=0A= =0A= for (i =3D0; i <=3D inStr.length; i++)=0A= {=0A= outStr =3D inStr.charAt(i) + outStr=0A= }=0A= =0A= return outStr=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function reverseAndReplaceString (inStr, findStr, newStr)=0A= {=0A= return reverseString(inStr).replace(findStr, newStr)=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function initUnObscureEmail (className, innerHTML)=0A= {=0A= =0A= try{=0A= if (window.addEventListener)=0A= window.addEventListener('load', function() {unObscureEmail = (className, innerHTML)}, false)=0A= else if (window.attachEvent)=0A= window.attachEvent('onload', function() {unObscureEmail = (className, innerHTML)})=0A= }catch(e){=0A= }=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function unObscureEmail (className, innerHTML)=0A= {=0A= try {=0A= if (typeof(unObscuredEmails) =3D=3D 'undefined')=0A= unObscuredEmails =3D new Array()=0A= =0A= if (! unObscuredEmails[className])=0A= {=0A= =0A= var elmnts =3D document.getElementsByTagName("span")=0A= for (var i =3D 0, len =3D elmnts.length; i < len; i++)=0A= {=0A= if (elmnts.item(i).className.indexOf(className, " ") = !=3D -1)=0A= {=0A= elmnts.item(i).innerHTML =3D innerHTML;=0A= unObscuredEmails[className] =3D true=0A= =0A= }=0A= }=0A= }=0A= }=0A= catch(e){=0A= }=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function pubMedDbLinkSubmit(control) {=0A= try{=0A= if (control.pubmedOption) =0A= control =3D control.pubmedOption=0A= if (control.options)=0A= location.href =3D = control.options[control.options.selectedIndex].value;=0A= }=0A= catch(e){}=0A= return false;=0A= }=0A= ------=_NextPart_000_0000_01C926E7.F0818250 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.ncbi.nlm.nih.gov/corehtml/jsutils/utils.1.js // = /web/private/htdocs/staff/sponomar/TEST/corehtml/jsutils/utils.1.js.orig=0A= =0A= var = utils=3D{KeyCode_TAB:9,KeyCode_DELETE:46,KeyCode_BACKSPACE:8,KeyCode_LEFT= _ARROW:37,KeyCode_RIGHT_ARROW:39,KeyCode_HOME:36,KeyCode_END:35,KeyCode_P= AGE_UP:33,KeyCode_PAGE_DOWN:34,KeyCode_UP_ARROW:38,KeyCode_DOWN_ARROW:40,= KeyCode_ESC:27,KeyCode_ENTER:13,KeyCode_SPACE:32,KeyCode_SHIFT_KEY:16,Key= Code_CTRL_KEY:17,KeyCode_ALT_KEY:18,KeyCode_LEFT_MS_WINDOWS_KEY:91,KeyCod= e_RIGHT_MS_WINDOWS_KEY:92,KeyCode_MS_MENU_KEY:93,bIsIe:0/*@cc_on+1@*/,isO= bject:function(a){return(a&&typeof = a=3D=3D'object');},isArray:function(a){return = this.isObject(a)&&a.constructor=3D=3DArray;},getParent:function(obj){if(o= bj){var = result=3Dobj.parentNode;while(result&&result.nodeType!=3D1)result=3Dresul= t.nextSibling;if(result)return result;}=0A= return null;},getFirstChild:function(obj){if(obj){var = result=3Dobj.firstChild;while(result&&result.nodeType!=3D1)result=3Dresul= t.nextSibling;if(result)return result;}=0A= return null;},getNextSibling:function(obj,tagName){if(obj){var = result=3Dobj.nextSibling;if(tagName){var = tn=3DtagName.toUpperCase();while(result&&result.tagName!=3Dtn)result=3Dre= sult.nextSibling;}else{while(result&&result.nodeType!=3D1)result=3Dresult= .nextSibling;}=0A= return result;}=0A= return null;},getPreviousSibling:function(obj,tagName){if(obj){var = result=3Dobj.previousSibling;if(tagName){var = tn=3DtagName.toUpperCase();while(result&&result.tagName!=3Dtn)result=3Dre= sult.previousSibling;}else{while(result&&result.nodeType!=3D1)result=3Dre= sult.previousSibling;}=0A= return result;}=0A= return null;},nextItem:function(item,nodeName){if(item=3D=3Dnull)return = null;var = next=3Ditem.nextSibling;while(next!=3Dnull){if(next.nodeName=3D=3DnodeNam= e)return next;next=3Dnext.nextSibling;}=0A= return null;},previousItem:function(item,nodeName){var = previous=3Ditem.previousSibling;while(previous!=3Dnull){if(previous.nodeN= ame=3D=3DnodeName)return previous;previous=3Dprevious.previousSibling;}=0A= return null},moveBefore:function(item1,item2){var = parent=3Ditem1.parentNode;parent.removeChild(item1);parent.insertBefore(i= tem1,item2);},moveAfter:function(item1,item2){var = parent=3Ditem1.parentNode;parent.removeChild(item1);parent.insertBefore(i= tem1,item2?item2.nextSibling:null);},insertAfter:function(parent,node,ref= erenceNode){parent.insertBefore(node,referenceNode.nextSibling);},removeC= hildren:function(oObj){if(!oObj||typeof = oObj!=3D"object")return;while(oObj&&oObj.hasChildNodes()){this.removeAllC= hildren(oObj.firstChild);oObj.removeChild(oObj.firstChild);}},removeAllCh= ildren:function(oObj){this.removeChildren(oObj);},getTextContent:function= (x){/*@cc_on return x.text;@*/return = x.textContent;},createCookie:function(name,value,days,path){if(days){var = date=3Dnew Date();date.setTime(date.getTime()+(days*24*60*60*1000));var = expires=3D'; expires=3D'+date.toGMTString();}else = expires=3D'';document.cookie=3Dname+'=3D'+value+expires+'; = path=3D'+(path?path:"/");},readCookie:function(name){var = nameEQ=3Dname+'=3D';var ca=3Ddocument.cookie.split(';');for(var = i=3D0;itest2){dim.w=3DparseInt(x.scrol= lWidth);dim.h=3Dtest1;}else{dim.w=3DparseInt(x.offsetWidth);dim.h=3Dtest2= ;}=0A= return dim;},getStyle:function(oObj,styleProp){var = res;if(oObj.currentStyle){res=3DoObj.currentStyle[styleProp];}=0A= if(typeof(res)!=3D"string"){if(oObj.style){res=3DoObj.style[styleProp];}=0A= if(typeof(res)!=3D"string"){if(document.defaultView){res=3Ddocument.defau= ltView.getComputedStyle(oObj,null).getPropertyValue(styleProp);}=0A= if(typeof(res)!=3D"string"){return null;}}}=0A= return res;},drawText:function(sText,sId,add){if(!sId)sId=3D"debug";var = obj=3Ddocument.getElementById(sId);if(obj){if(add)=0A= obj.innerHTML=3D"
"+sText;else=0A= obj.innerHTML+=3DsText;}},selectRange:function(oObj,iStart,iLength){if(!(= oObj&&oObj.value))return;if(oObj.createTextRange){var = oRange=3DoObj.createTextRange();oRange.moveStart("character",iStart);oRan= ge.moveEnd("character",iLength-oObj.value.length);oRange.select();}else = if(oObj.setSelectionRange){oObj.setSelectionRange(iStart,iLength);}=0A= oObj.focus();},getSelection:function(){var = text=3D"";if(window.getSelection){text+=3Dwindow.getSelection();}else = if(document.getSelection){text+=3Ddocument.getSelection();}else = if(document.selection){text+=3Ddocument.selection.createRange().text;}=0A= return text;},getPlural:function = x_Plural(iN,sSuffix){if(undefined=3D=3DsSuffix){return(iN>1?"s":"");}else= = if("y"=3D=3DsSuffix){return(iN>1?"ies":"");}else{return(iN>1?sSuffix+"s":= sSuffix);}},getPeriodToString:function(iDelta){var x=3D"Error, cannot = convert '"+iDelta+"'";var = sDir;iDelta=3DparseInt(iDelta);if(iDelta<0){sDir=3D" = before";iDelta=3D-iDelta;}else=0A= sDir=3D" ago";var iS=3DparseInt(iDelta/1000);var = iM,iH,iD;if(iS<60){x=3DiS+" = second"+this.getPlural(iS);}else{iM=3DparseInt(iS/60);if(iM<60){x=3DiM+" = minute"+this.getPlural(iM);}else{iH=3DparseInt(iM/60);if(iH<24){iM=3DiM-i= H*60;x=3DiH+" hour"+this.getPlural(iH)+" and "+iM+" = minute"+this.getPlural(iM);}else{iD=3DparseInt(iH/24);iH-=3DiD*24;x=3DiD+= " day"+this.getPlural(iD)+" and "+iH+" hour"+this.getPlural(iH);}}}=0A= return x+sDir;},isEmail:function(s){var = filter=3D/^([\w-]+(?:\.[\w-]+)*)@((?:[\w-]+\.)*\w[\w-]{0,66})\.([a-z]{2,6= }(?:\.[a-z]{2})?)$/i;return(filter.test(s))},addEvent_guid:1,addEvent:fun= ction(element,type,handler){if(!handler.$$guid)handler.$$guid=3Dthis.addE= vent_guid++;if(!element.events)element.events=3D{};var = handlers=3Delement.events[type];if(!handlers){handlers=3Delement.events[t= ype]=3D{};if(element["on"+type]){handlers[0]=3Delement["on"+type];}}=0A= handlers[handler.$$guid]=3Dhandler;element["on"+type]=3DhandleEvent;funct= ion handleEvent(event){var = returnValue=3Dtrue;event=3Devent||fixEvent(window.event);var = handlers=3Dthis.events[event.type];for(var i in = handlers){this.$$handleEvent=3Dhandlers[i];if(this.$$handleEvent(event)=3D= =3D=3Dfalse){returnValue=3Dfalse;}}=0A= return returnValue;};function = fixEvent(event){event.preventDefault=3DfixEvent.preventDefault;event.stop= Propagation=3DfixEvent.stopPropagation;return = event;};fixEvent.preventDefault=3Dfunction(){this.returnValue=3Dfalse;};f= ixEvent.stopPropagation=3Dfunction(){this.cancelBubble=3Dtrue;};return = handler.$$guid;},removeEvent:function(element,type,handler){if(element.ev= ents&&element.events[type]){delete = element.events[type][handler.$$guid];return handler.$$guid;}=0A= return = null;},preventDefault:function(e){if(e.preventDefault)e.preventDefault();= else = window.event.returnValue=3Dfalse;},getRelatedTarget:function(e){if(!e)var= e=3Dwindow.event;if(e.relatedTarget)return e.relatedTarget;else = if(e.toElement)return e.toElement;else if(e.fromElement)return = e.fromElement;},getTargetObj:function(eEvent){var oTarget;var = e=3DeEvent||window.event;if(e=3D=3Dnull)return = null;if(e.srcElement=3D=3Dnull)oTarget=3De.target;else = oTarget=3De.srcElement;while(oTarget&&oTarget.nodeType!=3D1)oTarget=3DoTa= rget.parentNode;return oTarget;},printObj:function(oObj,iLevel){var = s=3D"";var sIdent=3D"";if(!iLevel)iLevel=3D0;for(var = i=3D0;i";}=0A= return s;},jsLoader:{oLoaded:[],sBase:"",load:function(aScripts){var = oS=3Ddocument.getElementsByTagName("script");for(var = j=3D0;j");this.oLoaded.push(sNewSrc);}}}},inse= rtInHtml:function(text,obj){if(document.all){obj.innerHTML+=3Dtext;}else{= var range=3Ddocument.createRange();range.setStartAfter(obj);var = docFrag=3Drange.createContextualFragment(text);obj.appendChild(docFrag);}= },replaceInHtml:function(text,obj){if(document.all){obj.innerHTML=3Dtext;= }else{while(obj.hasChildNodes())obj.removeChild(obj.firstChild);var = range=3Ddocument.createRange();range.setStartAfter(obj);var = docFrag=3Drange.createContextualFragment(text);obj.appendChild(docFrag);}= }};String.prototype.trimSpaces=3Dfunction(trimMode){var = targetString=3Dthis;var = iPos=3D0;if(!trimMode)trimMode=3D0;if(trimMode=3D=3D0||trimMode=3D=3D1){i= f(targetString.charAt(iPos)=3D=3D" = "){while(targetString.charAt(iPos)=3D=3D" = ")iPos++;targetString=3DtargetString.substr(iPos);}}=0A= iPos=3DtargetString.length-1;if(trimMode=3D=3D0||trimMode=3D=3D2){if(targ= etString.charAt(iPos)=3D=3D" "){while(targetString.charAt(iPos)=3D=3D" = ")iPos--;targetString=3DtargetString.substr(0,iPos+1);}}=0A= return targetString;}=0A= function $(){var elements=3Dnew Array();for(var = i=3D0;i0) {=0A= var W=3DoMetadata.aView[0].W * oThis.fScale;=0A= for = (oThis.iScaleIndex=3D0;oThis.iScaleIndex