Journal of Clinical Investigation -- Resistance of = human glioblastoma multiforme cells to growth factor inhibitors is = overcome by blockade of inhibitor of apoptosis proteins

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J. Clin. Invest. = doi:10.1172/JCI34120.=20
Copyright =C2=A9 2008, The American Society for Clinical = Investigation

Research Article

Resistance of human glioblastoma = multiforme=20 cells to growth factor inhibitors is overcome by blockade of = inhibitor of apoptosis proteins

David S. = Ziegler¹,=20 Renee D. Wright¹, Santosh=20 Kesari², Madeleine E.=20 Lemieux¹, Mary A. = Tran³,=20 Monish Jain³, Leigh=20 Zawel³ and Andrew L. = Kung¹=20

¹Department of Pediatric = Oncology,=20 Dana-Farber Cancer Institute and Children=E2=80=99s Hospital = Boston, Harvard=20 Medical School, Boston, Massachusetts, USA.=20
²Department of Medical Oncology and = Department of=20 Cancer Biology, Dana-Farber Cancer Institute, and Department = of=20 Neurology, Brigham and Women=E2=80=99s Hospital, Harvard = Medical School,=20 Boston, Massachusetts, USA.
³Novartis = Institutes for=20 BioMedical Research, Cambridge, Massachusetts, USA.

Address correspondence to: = Andrew L.=20 Kung, Department of Pediatric Oncology, Dana-Farber Cancer=20 Institute, 44 Binney Street, Mayer 649, Boston, = Massachusetts 02115,=20 USA. Phone: (617) 632-5731; Fax: (617) 582-8096; E-mail: andrew_kung@dfci.harvard.edu= .=20

Published August 1, = 2008
Received for=20 publication October 2, 2007, and accepted in revised form = June 18,=20 2008.

Mu= ltiple=20 receptor tyrosine kinases (RTKs), including PDGFR, have been = validated as therapeutic targets in glioblastoma multiforme = (GBM),=20 yet inhibitors of RTKs have had limited clinical success. As = various=20 antiapoptotic mechanisms render GBM cells resistant to = chemo- and=20 radiotherapy, we hypothesized that these antiapoptotic = mechanisms=20 also confer resistance to RTK inhibition. We found that in = vitro=20 inhibition of PDGFR in human GBM cells initiated the = intrinsic=20 pathway of apoptosis, as evidenced by mitochondrial outer = membrane=20 permeabilization, but downstream caspase activation was = blocked by=20 inhibitor of apoptosis proteins (IAPs). Consistent with = this,=20 inhibition of PDGFR combined with small molecule = inactivation of=20 IAPs induced apoptosis in human GBM cells in vitro and had=20 synergistic antitumor effects in orthotopic mouse models of = GBM and=20 in primary human GBM neurospheres. These results demonstrate = that=20 concomitant inhibition of IAPs can overcome resistance to = RTK=20 inhibitors in human malignant GBM cells, and suggest that = blockade=20 of IAPs has the potential to improve treatment outcomes in = patients=20 with GBM.

Introduction

The = treatment of=20 malignant gliomas remains one of the greatest challenges = facing=20 adult and pediatric oncologists today. At the most severe = end of the=20 spectrum is glioblastoma multiforme (GBM), one of the most = malignant=20 of cancers, with a median survival of less than 12 months = and an=20 inherent resistance to both chemo- and radiotherapeutics = (1).=20 While initial treatment of GBM with surgery, radiotherapy, = and=20 chemotherapy often produces some palliation of symptoms, = these=20 tumors almost universally recur with an unrelenting = progression to=20 death. Despite great advances in our understanding of the = molecular=20 causes of GBM (2),=20 there has been very little improvement in outcomes for = patients with=20 GBM.

A variety of = growth=20 factor receptors are instrumental in the tumorigenesis of = gliomas=20 and have been validated as therapeutic targets. EGFR = amplification=20 is the most common genetic abnormality in adult high-grade = gliomas,=20 and EGFR overexpression has been demonstrated in up to 85% = of cases=20 (3).=20 Glioblastomas also often express EGFRvIII, a genomic = deletion=20 variant of EGFR that is constitutively active (4).=20 Similarly, IGF-1 receptor (IGF-1R) has been shown to be = abnormally=20 active in gliomas (5), and=20 its inhibition prevents tumor growth in preclinical models = (6).=20 Malignant gliomas also often exhibit overexpression of both = PDGF and=20 PDGFR, which contribute to tumor progression via an = autocrine or=20 paracrine loop (7=E2=80=93<= SPAN=20 class=3Dxref>9).=20 Antagonism of PDGFR with the tyrosine kinase inhibitor = imatinib=20 (also known as STI571 and Gleevec) in both in vitro and in = vivo=20 glioma models has demonstrated successful inhibition of = tumor growth=20 (10).=20

The = promising=20 laboratory results seen with receptor tyrosine kinase (RTK)=20 inhibitors in gliomas have thus far not translated into = clinical=20 success. Initial reports of the use of imatinib in patients = with=20 recurrent malignant gliomas reveal limited single-agent = activity=20 with few responders and a 6-month progression-free survival = of only=20 3% (11).=20 Only 10%=E2=80=9320% of patients have a clinical response to = EGFR kinase=20 inhibitors, and most responders subsequently exhibit rapid = tumor=20 progression (12,=20 13).=20

The = mechanisms of=20 resistance to RTK inhibition have not been fully elucidated = (14).=20 Tumor cells unresponsive to EGFR inhibitors are = characterized by=20 reduced induction of apoptosis (15).=20 Furthermore, while imatinib dramatically increases apoptosis = in=20 BCR-ABL=E2=80=93positive chronic myelogenous leukemia and in = gastrointestinal stromal tumors, it does not induce = apoptosis when=20 administered to glioblastoma cells either in vitro or in = vivo, even=20 at high concentrations (10,=20 16).=20 Multiple antiapoptotic mechanisms are known to be activated = in=20 glioma cells (17=E2=80=93= 19).=20 Mutation of the PTEN tumor suppressor results in activation = of the=20 PI3K/AKT pathway, which provides key antiapoptotic signals = (3, 20).=20 The proapoptotic activities of p53 are often lost due to = mutation or=20 overexpression of MDM2 (3, 21).=20 Multiple members of the BCL2 family are dysregulated (22).=20 The inhibitor of apoptosis proteins (IAPs) represent the = final=20 molecular blockade preventing apoptosis by inhibiting the = activity=20 of caspase-3, -7, and -9. IAPs have been shown to be highly=20 expressed in malignant gliomas (23,=20 24).=20 The IAP survivin has been identified in the majority of = malignant=20 gliomas, where its levels correlate inversely with prognosis = (25).=20 Peptides that inhibit IAPs have been shown to synergize with = TNF-related apoptosis-inducing ligand (TRAIL) and to enhance = apoptosis in glioma cells both in vitro and in vivo (26=E2=80=93= 28).=20

We = hypothesized that=20 the antiapoptotic mechanisms that render glioma cells = resistant to=20 cytotoxic agents (chemotherapy and radiotherapy) may also = modulate=20 their response to targeted therapies such as RTK inhibitors. = In this=20 study, we demonstrate that inhibition of PDGFR with imatinib = results=20 in activation of the apoptotic cascade, but downstream = blockade of=20 caspase activation prevents apoptosis. We show that the = apoptosis=20 repressor with CARD domain (ARC, also known as and referred = to=20 heareafter as nucleolar protein 3 [NOL3]) antiapoptotic = protein may=20 play a role in gliomas and is modulated by imatinib. We show = that=20 inhibition of the IAPs with LBW242, a small molecule that = binds to=20 and inhibits the BIR3 domain of IAPs, produces full-blown = apoptosis=20 in combination with PDGFR inhibition and results in = synergistic=20 antitumor efficacy in vitro and in vivo. These = results=20 suggest a potential strategy for increasing the clinical = efficacy of=20 RTK inhibitors in patients with gliomas and perhaps other=20 malignancies.

Results

Inhibition = of IAPs with LBW242. It has been proposed = that cancer=20 cells exist in a state of dynamic tension with a constant = burden of=20 proapoptotic signals counterbalanced by heightened = expression of=20 antiapoptotic proteins (29).=20 The IAPs constitute a final blockade of apoptosis through=20 sequestration of caspase-3, -7, and -9 (Figure 1A). = Upon=20 mitochondrial permeabilization, release of Smac/DIABLO into = the=20 cytoplasm results in binding to, and inactivation of, IAPs. = Since=20 IAPs are overexpressed in gliomas (23=E2=80=93= 25), it=20 is possible that blockade of IAPs alone may be sufficient to = shift=20 the balance towards apoptosis in glioma cells. The = small-molecule=20 IAP inhibitor LBW242 (Figure 1A) = was=20 developed through iterative binding optimization and = depeptidization=20 of the aminoterminal 4 amino acids of Smac, which is = necessary and=20 sufficient for binding to the BIR3 domain of IAPs (30). To=20 confirm that LBW242 does in fact effectively function as a = Smac=20 mimetic, we first performed a FRET-based competition assay = that=20 measured the ability of LBW242 to compete with Smac for = binding to=20 the BIR3 domain of XIAP. LBW242 inhibited the interaction of = full-length Smac to XIAP in a well-behaved sigmoidal = dose-response=20 relationship. To confirm the functional significance of the = binding=20 of LBW242 to IAPs, we next assessed the effect of LBW242 = binding on=20 caspase activity in a cell-free system. In an assay in which = the=20 activity of caspase-9 was blocked by recombinant XIAP-BIR3,=20 increasing doses of LBW242 resulted in caspase-9 activation = with=20 subsequent activation of caspase-3 and cleavage of a = fluorogenic=20 substrate (Figure 1C). =

Figure 1 Struct= ure=20 and function of LBW242. (A) Schematic of the = apoptotic=20 pathway with structure and site of action of LBW242, which = binds to=20 the IAPs and prevents their neutralization of the caspases.=20 (B) LBW242 competes with full-length Smac for = occupancy of=20 the XIAP-BIR3 surface groove, as assessed by a time-resolved = fluorescence energy transfer assay. (C) LBW242 = overcomes=20 XIAP-BIR3=E2=80=93mediated repression of caspase-3 activity = in a cell-free=20 extract, resulting in activation of caspase-3 and cleavage = of a=20 fluorogenic substrate. (D) LN827 cells treated with = the=20 indicated concentrations of LBW242 for 4 hours reveal no = change in=20 cellular levels of XIAP or caspase-9 (input). = Immunoprecipitation of=20 caspase-9 followed by immunoblot analysis revealed = dose-dependent=20 decrease in associated XIAP (IP caspase-9). (E and = F)=20 Densitometric analysis with data expressed relative to = vehicle=20 controls. (G) LBW242 concentrations in plasma, brain, = and=20 tumor of 3 SK-OV-3 tumor=E2=80=93bearing nude mice after 14 = days of daily=20 parenteral dosing of LBW242 (50 mg/kg), measured 4 hours = following=20 the final dose. Data represent mean =C2=B1 SEM for plasma = and tumor, and=20 the average of pooled samples for brain. (H) U87 = cells were=20 treated in triplicate with the indicated concentrations of = LBW242.=20 Relative cell numbers were assessed by=20 = 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)= -2H-tetrazolium,=20 inner salt (MTS) assay (see Methods). Data points represent = the mean=20 =C2=B1 SEM.

Because several=20 previously reported peptide IAP inhibitors have been = confounded by=20 their limited cellular and tissue penetration in a variety = of tumors=20 (26,=20 31=E2=80=93= 33), we=20 next assessed the effects of LBW242 in intact cells. LN827 = glioma=20 cells were exposed to LBW242 for 4 hours, and then = endogenous=20 caspase-9 was immunoprecipitated from whole cell extracts. = Although=20 LBW242 did not have any effect on the overall levels of = caspase-9,=20 or XIAP (Figure 1, D = and E),=20 the abundance of endogenous XIAP bound to caspase-9 was = reduced in=20 cells treated with LBW242 (Figure 1, D = and F).=20 These results establish the cellular permeability of LBW242 = and the=20 ability of LBW242 to disrupt endogenous binding of IAPs to = caspase-9=20 in intact cells.

To = determine=20 the achievable tissue concentrations of LBW242 in the in = vivo=20 setting, we administered LBW242 parenterally to mice at a = dose of 50=20 mg/kg/d. After 14 days of daily dosing, LBW242 achieved a = long-term=20 steady-state concentration that exceeded 60 =CE=BCM in = tumors (Figure 1G). = For=20 treatment of intracranial tumors, the blood-brain barrier = (BBB) is=20 an impediment to drug bioavailability. We found that LBW242 = was able=20 to cross even the intact BBB and achieve tissue = concentrations of=20 approximately 25 =CE=BCM in normal brain (Figure 1G). = The BBB is=20 at least partially disrupted within brain tumors (34),=20 suggesting that achievable brain tumor levels exceed 25 = =CE=BCM. Prior=20 studies have demonstrated the ability of LBW242 to inhibit = the=20 growth of hematologic malignancy cell lines as a single = agent with=20 IC₅₀ values in the 10=E2=80=9330 =CE=BCM range = (30). We=20 assessed the effect of LBW242 on glioma cell proliferation = in=20 vitro and found no stand-alone effects on the growth = of U87=20 cells (Figure 1H) = or LN827=20 cells (data not shown) up to concentrations of 50 =CE=BCM. = U87 (WT p53,=20 mutant PTEN, p16 and p14 deleted) and LN827 (p53 hemizygous, = mutant=20 PTEN, p16 and p14 deleted) (21)=20 glioma cell lines were selected for study because of their = robust in=20 vitro and orthotopic in vivo growth. U87 cells are further = known to=20 be dependent upon a PDGFR autocrine signaling loop (35).=20 Since in vivo steady-state tissue levels of LBW242 exceed = 25=E2=80=9360 =CE=BCM,=20 since there were no stand-alone effects on glioma growth up = to 50=20 =CE=BCM, and since caspase activity was most efficiently = reversed in=20 vitro at 50 =CE=BCM concentrations, we used a standardized = concentration=20 of 50 =CE=BCM for all subsequent combination studies.

Effects=20 of PDGFR and IAP inhibition on glioma cell growth.=20 Although IAP inhibition had no = monotherapeutic=20 activity, we hypothesized that apoptosis might be achieved = by=20 simultaneously increasing proapoptotic signals. Since PDGFR = has a=20 well-established role in gliomagenesis, and since withdrawal = of=20 growth factor signaling is proapoptotic in many systems = (36), we=20 assessed the combined effects of IAP and PDGFR inhibition on = cell=20 growth. As a single agent, imatinib inhibited cell growth at = doses=20 of 20 =CE=BCM or more (Figure 2A). = The=20 addition of LBW242, which had no effect on cell growth = alone,=20 resulted in a shift in the imatinib dose-response curve = toward=20 increased sensitization in LN827 and U87 cells (Figure 2A). = Over 4=20 days of treatment, only mild cytostasis is apparent with = either=20 imatinib or LBW242 alone, compared with frank cell death in = cells=20 treated with both agents (Figure 2B). =

Figure 2 Synerg= istic=20 effects of LBW242 and imatinib. (A) U87 and = LN827=20 cells were treated with the indicated concentrations of = imatinib in=20 combination with LBW242 (50 =CE=BCM) or DMSO control. Cell = numbers were=20 determined 72 hours later via MTS. Data are expressed as = mean =C2=B1 SEM=20 of triplicates. Similar results were observed in >3 = independent=20 experiments. (B) U87 and LN827 cells were seeded in = 96-well=20 plates and treated with LBW242 (50 =CE=BCM), imatinib (8 = =CE=BCM), LBW242 plus=20 imatinib, or DMSO control. The number of viable cells was = measured=20 via MTS assay after 24, 48, 72, and 96 hours. The data are = expressed=20 relative to the first day of treatment and are represented = as the=20 mean =C2=B1 SEM of triplicates. (C) Serum-starved = LN827 cells were=20 treated for 90 minutes with dosages of imatinib and LBW242 = as=20 indicated. Levels of PDGFR and phospho-PDGFR were measured = following=20 immunoprecipitation and immunoblotting. (D) U87 and = LN827=20 cells were seeded in 96-well plates and treated with the = PDGFR=20 inhibitor AMN107 at the dosages indicated in combination = with LBW242=20 (50 =CE=BCM) or DMSO control. Cellular proliferation was = measured via MTS=20 assay after 72 hours of incubation. Data are represented as = the mean=20 =C2=B1 SEM or triplicates.

Since = small=20 molecule kinase inhibitors are not monospecific, we = questioned=20 whether the observed effects were mediated through = inhibition of=20 PDGFR or through off-target effects on other kinases. While=20 treatment with imatinib had no effects on the overall = abundance of=20 PDGFR, the activation state of PDGFR was almost completely = abolished=20 by imatinib at 2.5 =CE=BCM in LN827 cells (Figure 2C). = When=20 administered as monotherapy, inhibition of LN827 cell growth = was=20 observed at imatinib concentrations of 20 =CE=BCM or more = (Figure 2A). = In=20 contrast, the synergistic effect on cell growth when = imatinib was=20 combined with LBW242 was observed at imatinib concentrations = of=20 approximately 1.25=E2=80=932.5 =CE=BCM (Figure 2A). = The=20 correlation of dosages causing PDGFR inhibition and = synergistic=20 inhibition of tumor growth suggests that the response seen = occurred=20 as a result of PDGFR inhibition. LBW242 had no effect on = PDGFR=20 abundance or activity (Figure 2C), = suggesting=20 that the synergistic effects of the combination are not due = to=20 LBW242 potentiating the inhibitory effects of imatinib on = PDGFR=20 activation.

To = further=20 confirm that the synergy observed resulted from PDGFR = inhibition, we=20 also tested the combination of LBW242 with an alternative = PDGFR=20 kinase inhibitor AMN107 (nilotinib; Figure 2D) = (37). A=20 synergistic inhibition of cell growth was again apparent = with the=20 combination treatment. Similar results were also seen when = LBW242=20 was tested in combination with the PDGFR inhibitor dasatinib = (data=20 not shown). Together, these results demonstrate that = inhibition of=20 IAPs in glioma cells has little stand-alone activity but = synergizes=20 with inhibition of PDGFR, which is known to play a key role = in=20 gliomagenesis. Stand-alone activity was observed with = imatinib=20 alone, but only at concentrations more than 10-fold above = that=20 required for PDGFR inhibition, suggesting that off-target = inhibition=20 of other kinases contributes to this single agent activity. =

Imatinib=20 activates the intrinsic pathway, but apoptosis requires = concomitant=20 blockade of IAPs. Given the established role = for=20 PDGFR in gliomas, and in light of the above results, we = hypothesized=20 that PDGFR inhibition may produce a proapoptotic signal that = is=20 counteracted by downstream antiapoptotic proteins. Multiple = upstream=20 proapoptotic signals converged at the level of the = mitochondria,=20 resulting in mitochondrial outer membrane permeabilization = (MOMP)=20 and release of the proapoptotic mediators cytochrome = c and=20 Smac/DIABLO (Figure 1A). = Therefore,=20 we studied whether imatinib induced MOMP, by measuring the=20 cytoplasmic levels of cytochrome c and Smac/DIABLO. = In LN827=20 cells, imatinib at 10 =CE=BCM, which had no effects on cell = growth=20 (Figure 2, A=20 and B), led to a significant increase in both cytoplasmic = cytochrome=20 c and Smac/DIABLO (Figure 3A). = Consistent=20 with its mechanism of action, LBW242 had no appreciable = effect on=20 cytochrome c or Smac/DIABLO levels, either as a = single agent=20 or in combination with imatinib (Figure 3A). = The=20 concentration of imatinib at which MOMP was observed was 2.5 = =CE=BCM=20 (Figure 3A),=20 which coincided with the concentration at which PDGFR = activity was=20 inhibited (Figure 2C) = and where=20 synergistic killing with LBW242 was observed (Figure 2A) = in LN827=20 cells.

Figure 3 PDGFR = and IAP inhibition combine to enhance caspase activity and = activate=20 apoptosis in glioma cells. (A) LN827 cells = were=20 treated with drugs as indicated for 48 hours, following = which the=20 cellular cytoplasm was separated from mitochondria. The = cytosol was=20 collected and subjected to immunoblotting for cytochrome = c=20 and Smac/DIABLO. (B) LN827 and U87 cells were treated = with=20 imatinib at the dosages indicated for 48 hours in = combination with=20 LBW242 (50 =CE=BCM) or DMSO control. Caspase-3/7 activity is = expressed=20 relative to controls as mean =C2=B1 SEM of triplicates. = *P <=20 0.01, 2-tailed Student=E2=80=99s t test. (C) = Apoptosis was=20 measured as the proportion of cells staining positive for = annexin V=20 after 72 hours of incubation with LBW242 (50 =CE=BCM) in = combination with=20 or without imatinib (10 =CE=BCM) or AMN107 (5 =CE=BCM). = Cells to the left of=20 the divider in each panel are negative for annexin V, and = positive=20 cells are to the right. The number in the upper right = corners=20 indicates the percentage of annexin V=E2=80=93positive cells = in each=20 treatment group. Similar results were obtained in 3 = independent=20 experiments.

Although=20 imatinib induced MOMP (Figure 3A), = there was=20 no activation of caspase-3 or -7 when cells were treated = with=20 imatinib alone (Figure 3B). = The=20 addition of LBW242 resulted in significant activation of = caspase-3/7=20 activity (Figure 3B). = To=20 determine if the synergistic activation of caspase-3/7 = activity=20 resulted in apoptosis, we measured the number of cells = staining=20 positive with annexin V. PDGFR inhibition with imatinib = alone and=20 IAP inhibition with LBW242 alone caused minimal change over = the=20 basal level of apoptosis, but the combination of imatinib = and LBW242=20 resulted in synergistic induction of apoptosis (Figure 3C). = A small=20 increase in apoptosis was apparent with AMN107 alone, but = again the=20 addition of LBW242 resulted in the majority of tumor cells=20 undergoing apoptosis (Figure 3C). =

Recent reports=20 have suggested that IAP inhibitors regulate the activity of = the=20 extrinsic apoptotic pathway in certain tumor types (38=E2=80=93= 40). We=20 therefore assessed the effect of imatinib with or without = LBW242 on=20 caspase-8 activity but found no significant changes = (Supplemental=20 Figure 1; supplemental material available online with this = article;=20 doi: 10.1172/JCI34120DS1), suggesting = that the=20 mechanism of synergy is limited to the intrinsic pathway. = Together,=20 these results establish that imatinib activates the = intrinsic=20 apoptosis pathway and MOMP but that caspase-3 and -7 are not = activated unless the IAPs are simultaneously blocked with = LBW242.=20 The combination of PDGFR and IAP inhibition produces = synergistic=20 induction of apoptosis.

RTK and=20 IAP inhibition activates caspases and suppresses tumor = growth=20 independently of Akt. Several RTKs have been=20 implicated in gliomagenesis, and we wondered whether the = synergistic=20 effects of PDGFR and IAP inhibition could be generalized to = other=20 growth factor receptors. First we assessed the combination = of IAP=20 inhibition and blockade of IGF-1R with NVP-AEW541, a highly = specific=20 IGF-1R kinase inhibitor (41).=20 The combination of AEW541 and LBW242 led to caspase-3/7 = activation=20 and synergistically inhibited tumor cell growth = (Supplemental Figure=20 2A). Next we tested blockade of EGFR with a dual EGFR and = HER2=20 kinase inhibitor PKI166 (42).=20 PKI166 as a single agent had a proapoptotic effect with = increased=20 levels of caspase-3/7 activation. However the addition of = IAP=20 inhibition led to enhanced caspase-3/7 activation and a = correlative=20 enhanced inhibition of glioma cell proliferation = (Supplemental=20 Figure 2B). It is known that glioma cells lose = overexpression of=20 EGFR in culture (21),=20 which may explain the overall modest effects observed.

Because PDGFR,=20 EGFR, and IGF-1R all activate Akt, and since Akt provides = key=20 antiapoptotic signals, we asked whether the demonstrated = induction=20 of apoptosis and inhibition of cell growth occur secondary = to Akt=20 inactivation. As shown in Figure 4A, = Akt is=20 tonically phosphorylated in LN827 cells. Administration of = imatinib=20 with or without LBW242 did not inhibit Akt phosphorylation, = nor did=20 it inhibit the downstream phosphorylation of BAD (Figure 4A).=20 Furthermore, the combination of LBW242 and the specific Akt=20 inhibitor triciribine did not demonstrate any notable = synergistic=20 effect on either caspase-3/7 activation or tumor cell = proliferation=20 (Figure 4B).=20 Thus the synergy between growth factor inhibition and IAP = inhibition=20 appears to occur independently of Akt status. It should be = noted=20 that these studies were done in the presence of serum and in = cells=20 that are PTEN deficient (21),=20 indicating only that Akt signaling is not attenuated under = these=20 conditions, not that PDGFR does not signal through Akt. =

Figure 4 Imatin= ib=20 induces apoptosis independent of Akt. (A) = LN827 cells=20 were treated with imatinib with or without LBW242, as = indicated. No=20 appreciable effects on Akt activation were apparent after 6 = hours of=20 treatment, as assessed by Ser473 phosphorylation. No effects = on=20 total or Ser112 phosphorylated BAD were apparent at 24 or 48 = hours.=20 (B) LN827 cells were treated with the Akt inhibitor=20 triciribine at the dosages indicated and with LBW242 (50 = =CE=BCM) or=20 DMSO. Caspase-3/7 activity was measured at 48 hours and = total cell=20 number at 72 hours. (C) Effects of imatinib with or = without=20 LBW242 on p42/44 activation were assessed after 6 hours. = (D)=20 Effects of imatinib with or without LBW242 on BCL2 family = members=20 were assessed at the indicated times. In all cases, no = significant=20 differences were apparent.

We = next tested=20 for alternative mechanisms by which PDGFR inhibition may = lead to=20 activation of the apoptotic pathway and MOMP. Because Erk = 1/2 is=20 another downstream target of growth factor receptors, we = assessed=20 its phosphorylation status and found that treatment with = imatinib=20 did not inhibit Erk 1/2 phosphorylation (Figure 4C). = We also=20 investigated whether treatment with imatinib led to a change = in=20 expression of a number of anti- or proapoptotic members of = the BCL2=20 family of proteins. However, we were unable to detect any=20 significant change in the broad range of proteins tested = (Figure 4D). =

To = more=20 comprehensively assess the effect of imatinib on a broad = number of=20 pro- and antiapoptotic mediators, we assessed mRNA = expression using=20 a 96-well quantitative RT-PCR microarray format as described = previously (43).=20 Treatment with imatinib 10 =CE=BCM resulted in a significant = change in=20 the expression of only 1 gene tested =E2=80=94 NOL3 = (Supplemental Figure 3).=20 Imatinib was found to decrease NOL3 mRNA abundance in = 7=20 individual multi-well screens. NOL3 encodes the = antiapoptotic=20 protein ARC, which is known to be highly expressed in normal = cardiac, skeletal, and neurological tissue (44,=20 45). An=20 independent quantitative RT-PCR analysis confirmed that = imatinib=20 significantly reduced NOL3 mRNA expression (Figure 5A). = Western=20 blot confirmed that the reduction in NOL3 transcription over = time=20 led to a correlative decrease in NOL3 protein levels, but = not of=20 other antiapoptotic proteins (Figure 5B). =

Figure 5 NOL3=20 is expressed in gliomas and is modulated by imatinib. = (A) Quantitative RT-PCR evaluation of NOL3 = mRNA=20 expression in LN827 cells following treatment with 10 = =CE=BCM imatinib.=20 Data represent mean =C2=B1 SEM of triplicates. *P = < 0.01,=20 2-tailed Student=E2=80=99s t test. (B) Western = blot showing=20 NOL3 protein levels in LN827 cells following treatment with = imatinib=20 10 =CE=BCM for the indicated times. (C) Comparison of = NOL3=20 mRNA expression levels in normal brain tissue, compared with = GBM=20 specimens. P values were calculated using unpaired = t=20 test with Welch's correction. Data values were obtained from = the=20 GSE4290 dataset (see Methods). (D) Comparison of = NOL3=20 mRNA expression levels in grade III, grade IV, and recurrent = high-grade gliomas, with P values calculated using = the 1-way=20 ANOVA test. Data values were obtained from the GSE4271 = dataset (see=20 Methods). (E) Kaplan-Meier survival curves for = patients with=20 high-grade gliomas based on NOL3 expression level. Results = were=20 separated above or below the median NOL3 level, and P = values=20 were calculated by the log-rank test. Data values were = obtained from=20 the GSE4271 dataset. (F) Western blot showing NOL3 = protein=20 levels in 293T cells following transfection with NOL3 = plasmid.=20 (G) LN827 cells were transfected with CD19 plasmid = and either=20 NOL3 plasmid or control vector. Cells were then treated with = LBW242=20 50 =CE=BCM plus imatinib 10 =CE=BCM or with vehicle control = for 72 hours.=20 Cells were stained with annexin V=E2=80=93PE and CD19-FITC = antibodies and=20 analyzed by flow cytometry, with CD19 used as a marker of = successful=20 transfection and annexin V=E2=80=93PE as a marker of = apoptosis. P=20 values were calculated by 2-tailed Student=E2=80=99s = t test.=20 (H) LN827 cells were transfected with 50 nM NOL3 = siRNA,=20 control (CT) siRNA, or Lipofectamine 2000 only (Nil). = Western blot=20 was performed for NOL3 protein after 72 hours, with all = samples on a=20 single gel but not in contiguous wells. (I) LN827 = cells were=20 transfected with either control or NOL3 siRNA. LBW242 50 = =CE=BCM was=20 added 5 hours after transfection. Apoptosis was determined = by=20 annexin V and PI staining after 72 hours of treatment. = (J)=20 LN827 cells were similarly treated with etoposide 50 = =CE=BCg/ml for 48=20 hours. P values were calculated using the 2-tailed = Student=E2=80=99s=20 t test.

A = role for NOL3=20 in gliomas has not to our knowledge been previously = described. To=20 determine the clinical relevance of NOL3 in malignant = gliomas, we=20 evaluated the expression of NOL3 utilizing previously = published mRNA=20 expression data (46,=20 47). We=20 found that NOL3 was significantly overexpressed in malignant = gliomas=20 when compared with non-tumor brain tissue (Figure 5C). = Evaluation=20 of NOL3 expression in subsets of malignant glioma specimens = revealed=20 increasing expression with worsening grade of tumor (Figure = 5D). = Similarly,=20 high expression of NOL3 in tumor specimens correlated with = inferior=20 patient survival (Figure 5E). =

We = next=20 investigated whether modulating NOL3 expression had an = impact on the=20 observed synergy between imatinib and LBW242. First we = ectopically=20 expressed NOL3 in LN827 cells (Figure 5F) = and=20 assessed the effects on the induction of apoptosis by the=20 combination of imatinib and LBW242. Transfection with NOL3 = led to a=20 marginal decrease in basal levels of apoptosis but had a far = more=20 significant impact on the proapoptotic effects of treatment = with=20 LBW242 and imatinib, with a 30% reduction in the number of = cells=20 undergoing apoptosis when compared with control cells = (Figure 5G).=20 Conversely, to test the antiapoptotic effects of NOL3, we = assessed=20 whether decreasing NOL3 expression alone was sufficient to = sensitize=20 cells to LBW242. siRNA knockdown of NOL3 led to decreased = protein=20 abundance (Figure 5H). = While NOL3=20 depletion alone did not significantly increase apoptosis = (Figure 5I), = depletion=20 of NOL3 combined with LBW242 resulted in a significant = increase in=20 cellular apoptosis (Figure 5I). = In=20 contrast, NOL3 depletion had no effect on the induction of = apoptosis=20 by etoposide (Figure 5J). = Taken=20 together, these results show that NOL3 expression is = associated with=20 glioma progression in patients, that ectopic expression of = NOL3 can=20 exert antiapoptotic effects in glioma cells, and that = decreased=20 expression may contribute to the proapoptotic effects of = imatinib=20 treatment. Since modulation of NOL3 expression only = partially=20 reverses the effects of imatinib and LBW242, it is likely = that other=20 effectors of apoptosis are important for mediating the full = effects=20 of this combination.

PDGFR=20 inhibition synergizes with IAP inhibition to suppress glioma = growth=20 in vivo and in primary human glioma neurospheres. = To=20 extend these findings in vivo, we next tested the = combination of=20 growth factor inhibition and IAP inhibition in an orthotopic = glioma=20 model. LN827 cells were stereotactically implanted into the = brains=20 of mice. Tumor burden was serially assessed by = bioluminescence=20 imaging, which has previously been shown to be highly = correlated=20 with tumor volume (48,=20 49).=20 Animals with established tumors, characterized by = logarithmically=20 increasing tumor burden, were divided into treatment = cohorts. One=20 group was treated with AMN107 at 100 mg/kg/d by oral gavage, = one=20 group with LBW242 at 50 mg/kg twice a day by oral gavage, = one group=20 with vehicle, and one group with the combination of LBW242 = and=20 AMN107. AMN107 was used in these studies due to its improved = pharmacokinetic properties in mice in comparison with = imatinib=20 (t_1/2 < 2 h). Consistent with the in=20 vitro studies, monotherapy with either AMN107 or = LBW242 alone=20 had no appreciable effect on tumor growth. In contrast, = animals=20 treated with both AMN107 and LBW242 had complete cessation = of tumor=20 growth (Figure 6, A = and B).=20 These results establish that combined inhibition of PDGFR = and IAP=20 produces synergistic antitumor efficacy in vivo in an = orthotopic=20 cell line glioma model.

Figure 6 AMN107= =20 and LBW242 combine to inhibit the growth of intracranial = LN827=20 orthografts and primary human glioblastoma neurospheres in = vitro and=20 in vivo. (A) Bioluminescent images from = control and=20 treated animals at the start and end of a 15-day treatment = with the=20 indicated doses of LBW242 and/or AMN107. (B) Tumor = burden was=20 assessed by serial bioluminescence imaging and expressed = relative to=20 the start of treatment. Data are mean values =C2=B1 SEM, = n =3D 6=20 animals per group. (C) Primary human glioma = neurospheres were=20 derived from 2 different patients (BT69, white bars; BT79, = black=20 bars) and were treated with imatinib and/or LBW242. = (D) Total=20 neurosphere numbers were counted and photographed 10 days = after=20 plating, with data expressed as relative mean =C2=B1 SD of = triplicates.=20 (E) Tumor neurospheres treated for 72 hours with = imatinib,=20 AMN107 (AMN), and/or LBW242 (LBW) were lysed and activated = caspase-3=20 was assessed by immunoblot. (F) Kaplan-Meier survival = curves=20 for mice implanted with primary human glioma orthografts. = Mice were=20 treated for 12 consecutive days with vehicle, AMN107, = LBW242, or a=20 combination of AMN107 and LBW242, with treatments beginning = 12 days=20 after implant. *P =3D 0.01, combination versus all = other=20 groups, for experimental day 60 and all time points = thereafter.=20

Animals treated=20 with LBW242 had no significant changes in weight (data not = shown),=20 suggesting no overt systemic toxicity. To further assess = toxicity,=20 animals treated with LBW242 for 2 weeks underwent full = necropsy.=20 Systematic evaluation of all major organ systems revealed no = histological changes indicative of drug toxicity, including = brain=20 (contralateral to tumor implants), eyes, thyroid, lungs, = liver,=20 spleen, gastrointestinal tract, kidneys, adrenal gland, = heart,=20 striated muscle, bone, bone marrow, or vasculature.

Since = it has=20 been suggested that xenografts grown from traditional = adherent serum=20 cultured cell lines may be poor predictors of clinical = outcome=20 (50), we=20 next examined this treatment combination in primary human = glioma=20 tumor neurospheres (51). In=20 neurospheres derived from 2 different patients with GBM, = LBW242 and=20 imatinib had stand-alone activity, and in combination they = had=20 additive effects in decreasing overall neurosphere numbers = (Figure=20 6C). To=20 further confirm this finding, we calculated the = combinatorial index=20 of imatinib plus LBW242 in a total of 5 neurosphere cultures = and 2=20 adherent cell lines. The effect was additive or synergistic = in all=20 but one of the cell cultures tested (Table 1). = The=20 morphological appearance of some neurospheres treated with = LBW242 in=20 combination with imatinib suggested aggregates of dead cells = (Figure=20 6D). To=20 specifically assess induction of apoptosis within these=20 neurospheres, lysates from treated neurospheres were = analyzed with=20 an antibody specific for the activated form of caspase-3. = Consistent=20 with the data derived from glioma cell lines, there was no=20 appreciable caspase-3 activation by imatinib or LBW242 = alone, and=20 minimal activation by AMN107 alone (Figure 6E). = However,=20 marked activation of caspase-3 was apparent when either = imatinib or=20 AMN107 was combined with LBW242 (Figure 6E). =

Table = 1 Com= binatorial=20 index for treatment with LBW242 plus imatinib in glioma=20 cells

To = determine=20 whether the same synergistic effect on primary glioma = neurospheres=20 could be recapitulated in the in vivo setting, we = orthotopically=20 implanted stem cell=E2=80=93enriched neurosphere cultures of = primary human=20 glioma cells intracranially in nude mice. After establishing = tumors=20 for 12 days, animals were divided into cohorts that were = treated=20 with vehicle, AMN107, LBW242, or a combination of AMN107 and = LBW242,=20 as described above. All animals treated with either vehicle = or=20 single agents died within 60 days. However, 3 of 7 mice = treated in=20 the combination arm remained alive and well at 125 days = follow-up,=20 with no evidence of either disease or treatment toxicity = (Figure 6F). = The=20 survival benefit at 60 days or more was highly statistically = significant (P =3D 0.01, 2-tailed Fisher=E2=80=99s = exact test). Taken=20 together, these results support the synergistic activity of = PDGFR=20 and IAP inhibition in both in vitro and in vivo models = derived from=20 glioma cell lines and primary human glioblastoma samples. =

Discussion

Novel = therapies for=20 malignant gliomas are desperately needed. In this study, we=20 demonstrate that RTK inhibitors activate the apoptotic = cascade,=20 including induction of MOMP, but that downstream = antiapoptotic=20 mechanisms prevent caspase activation and apoptosis. = Combination=20 treatment with the small molecule IAP inhibitor LBW242 and=20 inhibition of PDGFR resulted in synergistic induction of = apoptosis=20 and suppressed tumor growth in vitro, in vivo, and in = primary glioma=20 neurosphere models. Furthermore, the IAP inhibitor LBW242 = was=20 effectively combined with inhibitors that target the other = growth=20 factor RTKs, EGFR and IGF-1R. Thus, resistance to RTK = inhibitors was=20 overcome by concomitant inhibition of the IAPs.

These = results have=20 several potential implications. First, our results represent = what we=20 believe to be a novel approach to improve therapy with = growth factor=20 receptor inhibitors. While tyrosine kinase inhibitors hold = great=20 promise for improving outcomes, it is unlikely that a single = targeted therapy will ever form a definitive therapy in = malignant=20 gliomas, which are characterized by multiple altered = tumorigenic=20 pathways alongside widespread inter- and intratumoral = heterogeneity.=20 Despite the importance of growth factor pathways in glioma=20 tumorigenesis, clinical responses to growth factor receptor=20 inhibitors in glioma patients have been limited and, when = present,=20 often transient. Unlike chronic myelogenous leukemia, for = example,=20 which is primarily driven by a single dominant oncogene and = can=20 effectively be treated by targeting that defect alone, in = gliomas,=20 targeted therapies and indeed conventional therapies are = confounded=20 by the multitude of abnormalities that act to thwart = treatment=20 efficacy.

We have = shown that an=20 alteration in the apoptotic pathway reduces the effect of = treatments=20 targeting the growth factor pathways. That is, PDGFR = inhibition=20 alone results in activation of the intrinsic pathway and=20 mitochondrial permeabilization but does not cause caspase = activation=20 or apoptosis, indicating the presence of a downstream block = in the=20 apoptotic cascade. It is only following the addition of IAP=20 inhibition that an increase in caspase activity results, = with=20 subsequent apoptosis and an enhanced antitumor effect seen = both in=20 vitro and in vivo. Thus the strategy of targeting 2 separate = molecular pathways =E2=80=94 the aberrantly expressed IAPs = in combination=20 with the highly dysregulated growth factor pathway =E2=80=94 = effectively=20 suppresses tumor growth. Several recent reports have emerged = that=20 suggest that different SMAC mimetics can stimulate TNF = production=20 and propagate apoptosis via the extrinsic apoptotic pathway = in=20 certain tumor types (38=E2=80=93= 40).=20 Notably, this led to the ability of SMAC mimetics to induce = cell=20 death as single agents in some cell lines. In our = experiments LBW242=20 had no effect as a monotherapy and did not stimulate the = extrinsic=20 pathway, as assessed by measurement of caspase-8 activity.=20 Therefore, while the mechanism of apoptosis was limited to = the=20 intrinsic pathway in this study, therapeutic application of = IAP=20 inhibitors may result in antitumor efficacy through = pleiotropic=20 mechanisms.

Second, our = results=20 suggest that multiple factors need to be considered when = evaluating=20 responsiveness to growth factor receptor inhibitors. To = date, most=20 analyses have focused on receptor mutations and molecular = pathways=20 directly related to receptor signaling, such as PTEN status. = For=20 example, it has been shown that a clinical response to EGFR=20 inhibition is more likely in tumors that express the = EGFRvIII mutant=20 in association with an intact PTEN signaling pathway (4).=20 However, other studies have shown conflicting findings = =E2=80=94 in 1 report=20 the response was associated with EGFR amplification and = expression=20 but not EGFRvIII (52).=20 Our results suggest that distant downstream regulatory = mechanisms=20 may be just as important in determining response to therapy = both in=20 the laboratory and in the clinic. Indeed, the IAPs represent = one of=20 the most downstream blockades to apoptosis, and their = successful=20 inhibition illustrates the fact that targeting more distal = pathways=20 in combination with RTKs may be at least as beneficial as = focusing=20 purely on upstream signaling proteins. Moreover, our results = demonstrate what is to our knowledge a novel mechanism of = bypassing=20 molecular impediments to effective treatment. The synergy=20 demonstrated appears to occur independent of, and without = modulation=20 of, Akt status. Both cell lines tested have mutations in the = PTEN=20 tumor suppressor gene (21), a=20 factor not only associated with poor responses to growth = factor=20 receptor inhibitors, but also with an overall poor prognosis = (46). By=20 targeting the distal IAPs in combination with growth factor = receptor=20 inhibition, we have demonstrated a successful mechanism of = bypassing=20 the molecular PTEN/Akt blockade. Furthermore, the poor = clinical=20 responses seen with imatinib in glioma patient clinical = trials has=20 led to speculation that the lack of activity is due to poor=20 penetration of the BBB. Our results offer an alternative=20 explanation, that the RTK target is being inhibited but that = antiapoptotic mechanisms confer resistance to cell death, as = they do=20 in conventional chemotherapy and radiotherapy.

Third, we = have=20 identified a potential role for the antiapoptotic protein = NOL3 in=20 glioma biology. NOL3 has been described to be present in = normal=20 heart, skeletal muscle, and brain tissue and has been shown = to=20 inhibit both the intrinsic and extrinsic apoptotic pathways = (44,=20 45,=20 53). It=20 acts to block the caspase activity of caspase-2 and -8 = (44) but=20 has also been shown to regulate the release of cytochrome = c=20 from the mitochondria by interfering with Bax activation = (53).=20 NOL3 has only recently been demonstrated to be expressed in = various=20 cancer cell lines (54) and=20 to confer both chemo- and radioresistance in breast cancer = cells=20 (55).=20 Here we found, in a retrospective analysis, that NOL3 was=20 overexpressed in malignant gliomas when compared with normal = brain=20 tissue, with progressively higher levels of expression = detected in=20 worsening grades of tumor. High levels of expression = correlated with=20 poor prognosis and significantly inferior patient survival = (Figure=20 5E).=20 Prospective evaluation is needed to validate NOL3 as a = prognostic=20 indicator in gliomas. We have shown that PDGFR inhibition = with=20 imatinib leads to decreased abundance of NOL3 and that this = effect=20 may play a role in triggering the apoptotic pathway and thus = sensitizing cells to IAP inhibition.

Fourth, the = results=20 here raise the prospect that similar combinatorial = strategies may be=20 relevant in other tumors. A subset of ovarian cancer has = been shown=20 to over express PDGFR and to respond to treatment with = imatinib=20 (56).=20 However, as with gliomas, imatinib monotherapy is unable to = induce=20 apoptosis in ovarian cancers, and no efficacy has been = demonstrated=20 in clinical trials (56,=20 57).=20 Similarly, while imatinib has demonstrated efficacy in small = cell=20 lung cancers, no induction of apoptosis has been observed = (58).=20 Our results raise the prospect that a similar combinatorial = strategy=20 may be adopted to improve the response to PDGFR inhibition = in=20 cancers other than glioma. Moreover, the same may be applied = to=20 other RTK inhibitors in a variety of cancers. For example, = for=20 unknown reasons, tumor EGFR status does not predict the = response of=20 colorectal cancers to EGFR inhibitors (59).=20 Extrapolation of our results suggests that antiapoptotic = proteins=20 may be an important biomarker predictive of response to = treatment=20 with RTK inhibitors and that targeting the apoptotic pathway = in=20 conjunction with RTK inhibition may have the potential to = further=20 improve tumor responses.

Finally, = this=20 represents what we believe to be the first reported approach = to=20 targeting IAPs in gliomas that offers a feasible path for=20 translation to the clinic. Previous preclinical studies = validating=20 IAPs as therapeutic targets in gliomas have utilized = peptides, which=20 in some cases were administered by direct intratumoral = injection=20 (26,=20 31,=20 32).=20 While these innovative reports validated the notion of = targeting=20 IAPs, in terms of clinical translation, it is not feasible = to use=20 the peptides employed due to their instability and poor = cellular=20 permeability (60).=20 The development of small molecule inhibitors of IAPs = provides a more=20 tractable method for clinical translation. A small molecule = Smac=20 mimetic was previously shown to have synergistic effects = when=20 administered in vitro in combination with TRAIL in a = glioma=20 cell line, but was not tested in vivo (27,=20 28).=20 Our results establish the preclinical rationale for clinical = testing=20 of small molecule IAP inhibitors in combination with RTK = inhibitors=20 in patients with gliomas.

Methods

Cell=20 culture. The human glioma cell lines U87 and = LN827=20 were cultured in DMEM complete medium supplemented with 10%=20 heat-inactivated fetal calf serum, penicillin (100 U/ml) and = streptomycin (100 =CE=BCg/ml). Cells were cultured in a = humidified 10%=20 CO₂atmosphere at 37=C2=B0C and maintained in a = logarithmic=20 growth phase for all experiments.

Drugs.=20 LBW242, imatinib, AMN107, AEW541, and PKI166 = were=20 generously provided by Novartis Pharma. Triciribine was = purchased=20 from Calbiochem. Stock solutions of LBW242, AMN107, AEW541, = PKI166,=20 and triciribine were dissolved in DMSO (Sigma-Aldrich) and = stored at=20 =E2=80=9320=C2=B0C. Imatinib stock was dissolved in = double-distilled water and=20 stored at =E2=80=9320=C2=B0C. All drugs were diluted in = fresh medium immediately=20 prior to use.

Time-resolv= ed=20 fluorescence resonance energy transfer. = GST-XIAP-BIR3=20 (plasmid gift of Yigong Shi, Princeton University, = Princeton, New=20 Jersey, USA) was preincubated with LBW242 at varying = concentrations=20 in a 96-well format for 30 minutes. APC-labeled anti-GST = antibody=20 (PerkinElmer), europium-labeled streptavidin beads = (PerkinElmer),=20 and biotin-Smac were then added. Each well contained a final = concentration of 6.25 nM GST-XIAP-BIR3 with 3.5 nM = biotin-Smac, 1 nM=20 Eu-streptavidin, and 25 nM anti=E2=80=93GST-APC in the = presence or absence=20 of LBW242 at varying concentrations. Plates were incubated = for a=20 further 30 minutes and fluorescence read using an Envision=20 multilabel reader (PerkinElmer; emission filters: europium = 615 nM,=20 APC 665 nM, and optical module Lance Eu/APC Dual 452). The=20 IC₅₀ at which 50% of GST-BIR3 is released from=20 biotinylated Smac were determined using the XL-fit4 program = (IDBS=20 Software).

Cell-free=20 caspase assay. A cell-free extract was = prepared as=20 described previously (61). In=20 brief, 100 =CE=BCg of 293T cell extract (8 mg/ml) was mixed = with=20 cytochrome c (Sigma-Aldrich) and dATP (Gibco BRL) in = a=20 96-well plate format. Recombinant GST-XIAP-BIR3 fusion = protein was=20 added with or without LBW242 at the dosages indicated in = Figure 1C. = Hypotonic=20 lysis buffer was added to bring the final volume to 25 = =CE=BCl. The=20 contents were mixed and the plate incubated at 30=C2=B0C for = 30 minutes=20 to activate the extract. A cocktail of 7 =CE=BCl Ac-DEVD-AMC = (BD=20 Biosciences) caspase-3 substrate, 20 =CE=BCl 5=C3=97 = apoptosis buffer, and 48=20 =CE=BCl diH₂O was then added, plates incubated = for a further=20 30 minutes at 30=C2=B0C, and fluorescence read at 360/460 nm = on Cytofluor=20 II.

Measurement= =20 of LBW242 concentrations in vivo. Athymic = nude=20 (nu/nu) mice subcutaneously implanted with SK-OV-3 = xenograft=20 were administered i.v. a 50-mg/kg dose of LBW242 or vehicle = control=20 once daily for 14 days. Four hours after the last dose, = animals from=20 control and treated groups were sacrificed and tissues and = blood=20 samples collected. For quantitative analysis of LBW242, = individual=20 tumor samples were added with 5 parts (weight/volume) of PBS = (pH=20 7.4) and homogenized (Autogizer; Tomtec) at room = temperature. Blood=20 samples were treated with sodium EDTA anticoagulant and = further=20 centrifuged to obtain plasma.

Blank = plasma or=20 tissue homogenates from animals untreated with either = vehicle or=20 test compound were used to prepare calibration standards = from 0.5 to=20 500 =CE=BCM of LBW242 by a serial dilution method. Fifty = microliters of=20 plasma or tissue homogenate calibration standards and study = samples=20 were successively added with 25 =CE=BCl of 2 =CE=BCM = glyburide internal=20 standard solution and 0.4 ml of protein precipitation = solvent=20 mixture (acetonitrile/ethanol/acetic acid, 90:10:0.2, = vol/vol),=20 thoroughly vortexed for 3 minutes, and centrifuged (1,500 = g)=20 for 5 minutes. A 100-=CE=BCl aliquot of clear supernatant = was transferred=20 into a 96-well plate and 50 =CE=BCl of 0.1% acetic acid was = added and=20 mixed well, and a 10-=CE=BCl portion of the resulting = solution was=20 injected onto a HPLC/MS/MS system for quantitative analysis = of=20 LBW242. A C-18 reverse-phase HPLC column (Ace3 C18; 3.0 = =C3=97 50 mm;=20 3.5-=CE=BCm particle size; Mac Mod Analytical Inc.) eluted = with a=20 gradient mobile phase (solvent A, 0.1% formic acid in water; = solvent=20 B, 0.1% formic acid in acetonitrile) chromatographically = separated=20 LBW242 and internal standard from endogenous materials. The = effluent=20 mobile phase was introduced into a tandem mass spectrometry = detector=20 (API 4000; Applied Biosciences) to monitor LBW242 and = internal=20 standard via electrospray-positive ionization, multiple = reaction=20 monitoring mode. Calibration curves (0.5 to 500 =CE=BCM = concentration=20 range) of LBW242 in plasma or tumor using peak area ratio of = compound to internal standard generated with quadratic = regression=20 fit (Analyst software, version 4; Applied Biosystems) were = used for=20 quantification of test compound concentrations.

Cellular=20 proliferation assays. Cell proliferation = assays were=20 performed with CellTiter 96 Aqueous One Solution Cell = Proliferation=20 Assay (Promega) as per the manufacturer=E2=80=99s = recommendations. Briefly,=20 1 =C3=97 10³ cells were plated in 100 =CE=BCl of = medium in 96-well=20 microtiter plates and incubated for 24 hours. The = concentrations of=20 inhibitors (indicated in Figure 1H, = Figure 2, = and Figure=20 4B) were=20 added and the cells incubated for a further 48 to 72 hours. = Labeling=20 reagent (20 =CE=BCl) was added to each well and allowed to = incubate at=20 37=C2=B0C for 2 hours. The absorbance was then read at 490 = nm with a=20 96-well plate reader.

Caspase-3/7= =20 activity and caspase-8 activity assays. = Caspase-3/7=20 activity was measured with the Apo-One Homogenous = Caspase-3/7 Assay=20 kit (Promega) according to the manufacturer=E2=80=99s = protocol. Briefly, 1 =C3=97=20 10³ cells in 100 microliters of medium were = plated in=20 96-well microtiter plates and incubated for 24 hours. The = indicated=20 concentration of inhibitors was added and the cells = incubated for a=20 further 48 hours. Labeling reagent (100 =CE=BCl) was added = to each well.=20 Caspase-3/7 activity was measured after 6 hours=E2=80=99 = incubation on a=20 fluorescence plate reader, with an excitation wavelength of = 485 nm=20 and emission wavelength of 535 nm. Caspase-8 activity was = measured=20 with the Caspase-Glo 8 assay (Promega) according to the=20 manufacturer=E2=80=99s protocol. Cells were prepared as = above, 100 =CE=BCl of=20 labeling reagent was added to each well, and luminescence = was=20 measured after 2 hours of incubation on a plate-reading = luminometer.=20

Flow=20 cytometric and annexin V analysis. Cells (2.5 = =C3=97=20 10⁵) were plated in 60-mm plates in 2 ml of = medium and=20 cultured for 24 hours. The medium was removed and inhibitors = were=20 added in DMEM with 1% serum. Cells were cultured for a = further 72=20 hours, collected for analysis, washed twice in cold PBS, and = resuspended in 100 =CE=BCl of binding buffer containing an = annexin V=E2=80=93FITC=20 and propidium iodide mixture (Invitrogen) as per the = manufacturer=E2=80=99s=20 instructions. Before FACS analysis, an additional 400 = =CE=BCl of binding=20 buffer was added to the cell suspension. FACS analysis was = performed=20 on FACScan and gated to exclude cellular debris; 10,000 = events were=20 collected for each sample.

Antibodies = and western blotting. Cells were pretreated = with=20 inhibitors; washed twice in ice-cold PBS; lysed with RIPA = buffer=20 (Boston Bioproducts) containing 50 mM Tris-Cl (pH 7.4), 150 = mM NaCl,=20 1% NP-40, 0.5% sodium deoxycholate, and 0.1% SDS with added = 1 mM=20 EDTA, 1 mM sodium orthovanadate, 50 mM NaF, and Complete = Protease=20 Inhibitor cocktail (Roche Applied Science); vortexed for 5 = seconds;=20 and centrifuged at 16,100 g for 10 minutes at = 4=C2=B0C. Equal=20 amounts of protein were loaded onto 4%=E2=80=9312% = Bis-Tris-polyacrylamide=20 gel (Invitrogen), separated by electrophoresis, and = transferred to=20 nitrocellulose membranes (Invitrogen). Western blots were = probed=20 with =CE=B2-actin (Sigma-Aldrich), PDGFR-=CE=B2 antibody = (Abcam), and=20 phospho=E2=80=93PDGFR-=CE=B2 antibody, phospho-Akt, Bad, = phospho-Bad Ser112 and=20 Ser136, MCL-1, BCL2 (all from Cell Signaling), and NOL3 = C-Terminus=20 (Chemicon) as per the manufacturer=E2=80=99s instructions. = Blots were then=20 labeled with anti-rabbit or anti-mouse IgG-HRP antibody = (Vector=20 Laboratories) and visualized using an enhanced = chemiluminescence=20 system (Amersham) or electronic chemiluminescence (ChemiDoc = XRS=20 System; Bio Rad).

Immunoprec= ipitation=20 studies. For PDGFR immunoprecipitation, 5 = =C3=97=20 10⁵ cells were plated in 2 ml of medium in 60-mm = plates=20 and incubated overnight. Medium was removed and the cells = serum=20 starved for 24 hours. Inhibitors were added for 90 minutes = and the=20 cells then stimulated with serum for 5 minutes. Cells were = washed=20 twice with ice-cold PBS and lysed with RIPA buffer (Boston=20 Bioproducts) containing 50 mM Tris-Cl (pH 7.4), 150 mM NaCl, = 1%=20 NP-40, 0.5% sodium deoxycholate, and 0.1% SDS with added 1 = mM EDTA,=20 1 mM sodium orthovanadate, 50 mM NaF, and Complete Protease=20 Inhibitor cocktail (Roche Applied Science). Standardized = aliquots of=20 lysate were incubated with PDGF-=CE=B2 receptor antibody = (Abcam)=20 overnight at 4=C2=B0C and immobilized on Protein G Sepharose = (Amersham=20 Biosciences) for 1 hour. Beads were washed extensively with = buffer.=20 Samples were fractionated on SDS-PAGE, transferred to=20 nitrocellulose, and immunoblotted with = phospho=E2=80=93PDGFR-=CE=B2 antibody=20 (Cell Signaling) and PDGFR-=CE=B2 antibody (Abcam) as = described above.=20

For = caspase-9=20 immunoprecipitation, LN827 cells were treated with LBW242 or = DMSO=20 control for 4 hours. For each concentration of LBW242, = dishes (4 =C3=97=20 15 cm) were scraped into ice-cold lysis buffer (150 mM NaCl, = 1%=20 Triton-X, 50 =CE=BCM Tris-Cl (pH 8.0), 1 mM EDTA) with = Complete Protease=20 Inhibitor cocktail. Protein concentration was determined by = Bradford=20 Assay (BioRad), and 50 =CE=BCg of each lysate was removed as = the input.=20 Anti=E2=80=93caspase-9 antibody (BD Biosciences) was bound = overnight at 4=C2=B0C=20 and then immobilized on Protein G Sepharose for 1 hour. = Beads were=20 extensively washed with lysis buffer, fractionated and = transferred=20 to nitrocellulose as described above, and immunoblotted with = XIAP=20 (Cell Signaling), and caspase-9 (Cell Signaling) antibodies. = Image=20 analysis was performed using ImageJ (NIH) and expressed = relative to=20 DMSO controls.

Mitochondr= ial=20 permeabilization analysis. Cells (5 =C3=97 = 10⁵)=20 were seeded in each 6-cm plate and treated with drugs as = indicated=20 in Figure 3A. = Following=20 48 hours of incubation, cells were collected and the = mitochondria=20 separated from cytoplasm using a mitochondria isolation kit = (Pierce=20 Biotechnology) as per the manufacturer=E2=80=99s = instructions. The cytosolic=20 fraction was collected, and equal amounts of protein were=20 fractionated on SDS-PAGE, transferred to nitrocellulose, and = immunoblotted with cytochrome c antibody (BD = Biosciences =E2=80=94=20 Pharmingen), Smac/DIABLO antibody (Cell Signaling), and = =CE=B2-actin=20 antibody (Sigma-Aldrich) as described above.

Microarray= =20 analysis. LN827 cells (1 =C3=97 = 10⁵) were=20 plated in 6-cm plates and treated with imatinib 10 =CE=BCM = in DMEM plus=20 1% serum for 36 hours. Following treatment, cells were = harvested and=20 RNA extracted using RNeasy Mini kit (Qiagen), as per the=20 manufacturer=E2=80=99s instructions. Gene expression = profiling of the=20 apoptotic pathway was performed and analyzed using = RT²=20 Profiler PCR Array Human Apoptosis, catalog no. APHS-012B=20 (SuperArray Bioscience), as per the manufacturer=E2=80=99s = instructions.=20

Real-time = PCR. LN827 cells were treated in triplicate = with=20 imatinib 10 =CE=BCM or vehicle control for 15 hours, = harvested, and=20 homogenized using QIAshredder columns (Qiagen), and total = RNA was=20 extracted using RNeasy Mini kit (Qiagen) according to the=20 manufacturer=E2=80=99s protocol. Real-time PCR was then = conducted using 5 =CE=BCg=20 of RNA added to 10 U of Superscript III reverse = transcriptase=20 (Invitrogen), 5 =CE=BCM forward and reverse primers, and = 1=C3=97 SYBR Green=20 (Qiagen). Reactions were run and analyzed using the = Stratagene=20 Mx3000p instrument and software (Stratagene).

Gene=20 expression analysis. Normalized gene = expression data=20 was obtained from the Gene Expression Omnibus online = datasets=20 GSE4290 = (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=3DGSE4290)=20 and GSE4271=20 = (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=3DGSE4271), and=20 NOL3 expression levels were analyzed using GraphPad Prism 4 = software=20 (Figure 5E).=20

Plasmid=20 transfection. NOL3 plasmid (NM_003946; = Origene) was=20 tested in 293T cells after transfection using Lipofectamine = 2000=20 (Invitrogen). Cells were harvested after 24 hours and = subjected to=20 western blot for NOL3 protein. LN827 cells (1 =C3=97 = 10⁵ per=20 well of a 6-well plate) were cultured overnight, then = treated with=20 the transfection reagent Fugene 6 (Roche Applied Science) = with 3.2=20 =CE=BCg of either NOL3 plasmid or pcDNA3.1-HisC control = vector, plus 0.8=20 =CE=BCg of CD19 plasmid per well as an internal control for = transfection=20 efficiency. After 6 hours the incubation medium was replaced = and=20 cells were incubated overnight. The following day the medium = was=20 replaced with DMEM plus 1% serum, and cells were treated = with LBW242=20 and imatinib or vehicle control as indicated in Figure 5G. = After a=20 further 72 hours of incubation, cells were collected, = stained with=20 Annexin V=E2=80=93PE (BD Biosciences =E2=80=94 Pharmingen) = and CD19-FITC antibody,=20 and analyzed by flow cytometry.

siRNA=20 knockdown. LN827 cells were treated with=20 Lipofectamine 2000 (Invitrogen) and transfected with pooled = NOL3=20 siRNA (NM_003946; Dharmacon) or control siRNA (Dharmacon) = for 5=20 hours as per the manufacturer=E2=80=99s instructions. The = medium was changed=20 and replaced with DMEM and 1% serum plus imatinib 10 = =CE=BCM, LBW242 50=20 =CE=BCM, and/or vehicle control, as indicated in Figure 5, I = and J.=20 After 72 hours of incubation, cells were collected and = analyzed for=20 apoptosis as described above.

Tumor=20 cell line xenografts. Tumor cell lines were = harvested=20 in midlogarithmic growth phase and resuspended in PBS. = Homozygous=20 NCR nude mice (Charles River Laboratories) were anesthetized = i.p.=20 with ketamine hydrochloride at 150 mg/kg and xylazine at 12 = mg/kg=20 (Phoenix Pharmaceuticals). A small surgical incision along = the=20 midline was made to expose the calvarium, and the periosteum = was=20 removed with a sterile cotton swab. Mice were restrained in = a=20 stereotactic frame (Stoeltling), and a small burr-hole (size = 34;=20 Roboz) was created at 2 mm lateral and 2 mm posterior to the = bregma.=20 LN827-LN cells (5 =C3=97 10⁵) in 10 =CE=BCl PBS = were injected=20 through a 27-gauge needle over 3 minutes (3.3 =CE=BCl/min) = at 3 mm below=20 the dura. The incision was closed with wound clips (Becton=20 Dickinson; catalog no. 427631) and removed 5=E2=80=937 days = after surgery.=20

Mice = were=20 imaged at least twice after implantation of cells to = identify those=20 in which tumor burden increased over time. Three weeks after = implantation of LN827-LN cells, cohorts of 40 mice per = experiment=20 with approximately equivalent tumor bioluminescence were = divided=20 into equal control and treatment groups. Mice were treated = with 50=20 mg/kg of LBW242 per oral (PO) once daily and/or 100 mg/kg of = AMN107=20 PO daily for 14 days.

For = in vivo=20 imaging, mice were anesthetized, injected with d-luciferin at 50 = mg/ml i.p.=20 (Xenogen), and imaged with the IVIS Imaging System (Xenogen) = for=20 10=E2=80=93120 s, bin size 2. To quantify bioluminescence, = identical=20 circular regions of interest were drawn to encircle the = entire head=20 of each animal, and the integrated flux of photons (photons = per=20 second) within each region of interest was determined by = using the=20 LIVING IMAGE software package (LI Version 2.50; Xenogen=20 Corporation). Data were normalized to bioluminescence at the = initiation of treatment for each animal. All animal studies = were=20 performed under protocols approved by the Dana-Farber Cancer = Institute Animal Care and Use Committee.

Glioma=20 neurosphere assays. Collection and use of = fresh and=20 discarded human tumor tissue was approved by the Brigham and = Women=E2=80=99s=20 Hospital Institutional Review Board. After frozen section = diagnosis=20 of malignant glioma by the attending neuropathologist, tumor = material was grossly dissected from the tissue sample. = Portions of=20 the tumors were collected in chilled media for the studies = described=20 here, and other portions were allocated for paraffin = embedding for=20 histological diagnosis and for genotyping. Expansion of = tumor=20 material and propagation was accomplished by subcutaneous=20 implantation in NOD-SCID mice (cells were never grown on = plastic or=20 in FBS). When tumors reached approximately 1 cm in size, = tumors were=20 disaggregated and cells were counted and then reimplanted in = mice or=20 grown in serum-free media with EGF, FGF, and leukemia = inhibitory=20 factor, as described previously (51,=20 62) to=20 form tumor neurospheres. Imatinib (5 =CE=BCM) and LBW242 (50 = =CE=BCM) were=20 added 24 hours after plating, and tumor neurospheres were = counted 10=20 days after plating. The combinatorial indices for LBW242 and = imatinib were expressed as the ratio of observed/expected = cells=20 surviving, where the expected result was calculated as the=20 proportion of surviving cells following treatment with = LBW242 alone=20 multiplied by the proportion of cells following treatment = with=20 imatinib alone. For assessment of apoptosis, tumor = neurospheres were=20 preestablished for 7 days, imatinib and LBW242 were added, = and tumor=20 neurospheres were harvested 3 days later. Tumor neurospheres = were=20 lysed by resuspending in SDS-PAGE loading buffer and = homogenized by=20 centrifugation (Qiashredder; Qiagen). Immunoblot utilized a = cleaved=20 caspase-3 antibody (Cell Signaling).

For = the in=20 vivo experiments, hBT37 cells were resuspended in PBS at a=20 concentration of 20,000 viable cells/5 =CE=BCl PBS and = injected into the=20 right caudate as previously described (62).=20 Twelve days following tumor implantation, mice were divided = into 4=20 equal treatment groups and treated with vehicle, LBW242 (25 = mg/kg=20 i.p. daily), AMN107 (100 mg/kg PO daily), or a combination = of LBW242=20 and AMN107. The treatments were administered for 12 days, = following=20 which the animals were monitored for survival. Animals were=20 sacrificed at the onset of neurological symptoms or once = moribund.=20

Statistics= .=20 Student=E2=80=99s t test was = calculated using=20 Microsoft Excel. Log-rank test was calculated using GraphPad = Prism.=20 Fisher=E2=80=99s exact test was calculated using SPSS. All = P values=20 are 2 tailed. P values less than 0.05 were considered = significant.

Supplemental=20 data

View = Supplemental=20 data

Acknowledgments

This work = was=20 supported by grants from the Dana-Farber Cancer = Institute=E2=80=93Novartis=20 Drug Discovery Program (to A.L. Kung), the Royal = Australasian=20 College of Physicians Rowden White Fellowship (to D.S. = Ziegler), the=20 Hagerty Fund Research Award (to D.S. Ziegler, S. Kesari, and = A.L.=20 Kung), the Leonard Florence Brain Tumor Fund (to S. Kesari), = and the=20 Australian-American Fulbright Commission (to D.S. Ziegler). =

Footnotes

Nonstandard abbreviations used: BBB, blood-brain = barrier;=20 GBM, glioblastoma multiforme; IAP, inhibitor of apoptosis = protein;=20 IGF-1R, IGF-1 receptor; MOMP, mitochondrial outer membrane=20 permeabilization; NOL3, nucleolar protein 3; RTK, receptor = tyrosine=20 kinase.

Conflict of interest: The authors have declared = that no=20 conflict of interest exists.

Citation for this article:J. Clin. Invest.=20 doi:10.1172/JCI34120

David S. Ziegler=E2=80=99s present address is: Centre for = Children=E2=80=99s=20 Cancer and Blood Disorders, Sydney Children=E2=80=99s = Hospital and the=20 Children=E2=80=99s Cancer Institute Australia for Medical = Research,=20 Randwick, New South Wales, Australia.

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------=_NextPart_001_0023_01C8FF09.F88F7980-- ------=_NextPart_000_0006_01C8FF09.F88121A0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.jci.org/javascripts/prototype.js?1218554506 /* Prototype JavaScript framework, version 1.6.0=0A= * (c) 2005-2007 Sam Stephenson=0A= *=0A= * Prototype is freely distributable under the terms of an MIT-style = license.=0A= * For details, see the Prototype web site: http://www.prototypejs.org/=0A= *=0A= = *------------------------------------------------------------------------= --*/=0A= =0A= var Prototype =3D {=0A= Version: '1.6.0',=0A= =0A= Browser: {=0A= IE: !!(window.attachEvent && !window.opera),=0A= Opera: !!window.opera,=0A= WebKit: navigator.userAgent.indexOf('AppleWebKit/') > -1,=0A= Gecko: navigator.userAgent.indexOf('Gecko') > -1 && = navigator.userAgent.indexOf('KHTML') =3D=3D -1,=0A= MobileSafari: !!navigator.userAgent.match(/Apple.*Mobile.*Safari/)=0A= },=0A= =0A= BrowserFeatures: {=0A= XPath: !!document.evaluate,=0A= ElementExtensions: !!window.HTMLElement,=0A= SpecificElementExtensions:=0A= document.createElement('div').__proto__ &&=0A= document.createElement('div').__proto__ !=3D=3D=0A= document.createElement('form').__proto__=0A= },=0A= =0A= ScriptFragment: ']*>([\\S\\s]*?)<\/script>',=0A= JSONFilter: /^\/\*-secure-([\s\S]*)\*\/\s*$/,=0A= =0A= emptyFunction: function() { },=0A= K: function(x) { return x }=0A= };=0A= =0A= if (Prototype.Browser.MobileSafari)=0A= Prototype.BrowserFeatures.SpecificElementExtensions =3D false;=0A= =0A= if (Prototype.Browser.WebKit)=0A= Prototype.BrowserFeatures.XPath =3D false;=0A= =0A= /* Based on Alex Arnell's inheritance implementation. */=0A= var Class =3D {=0A= create: function() {=0A= var parent =3D null, properties =3D $A(arguments);=0A= if (Object.isFunction(properties[0]))=0A= parent =3D properties.shift();=0A= =0A= function klass() {=0A= this.initialize.apply(this, arguments);=0A= }=0A= =0A= Object.extend(klass, Class.Methods);=0A= klass.superclass =3D parent;=0A= klass.subclasses =3D [];=0A= =0A= if (parent) {=0A= var subclass =3D function() { };=0A= subclass.prototype =3D parent.prototype;=0A= klass.prototype =3D new subclass;=0A= parent.subclasses.push(klass);=0A= }=0A= =0A= for (var i =3D 0; i < properties.length; i++)=0A= klass.addMethods(properties[i]);=0A= =0A= if (!klass.prototype.initialize)=0A= klass.prototype.initialize =3D Prototype.emptyFunction;=0A= =0A= klass.prototype.constructor =3D klass;=0A= =0A= return klass;=0A= }=0A= };=0A= =0A= Class.Methods =3D {=0A= addMethods: function(source) {=0A= var ancestor =3D this.superclass && this.superclass.prototype;=0A= var properties =3D Object.keys(source);=0A= =0A= if (!Object.keys({ toString: true }).length)=0A= properties.push("toString", "valueOf");=0A= =0A= for (var i =3D 0, length =3D properties.length; i < length; i++) {=0A= var property =3D properties[i], value =3D source[property];=0A= if (ancestor && Object.isFunction(value) &&=0A= value.argumentNames().first() =3D=3D "$super") {=0A= var method =3D value, value =3D Object.extend((function(m) {=0A= return function() { return ancestor[m].apply(this, arguments) = };=0A= })(property).wrap(method), {=0A= valueOf: function() { return method },=0A= toString: function() { return method.toString() }=0A= });=0A= }=0A= this.prototype[property] =3D value;=0A= }=0A= =0A= return this;=0A= }=0A= };=0A= =0A= var Abstract =3D { };=0A= =0A= Object.extend =3D function(destination, source) {=0A= for (var property in source)=0A= destination[property] =3D source[property];=0A= return destination;=0A= };=0A= =0A= Object.extend(Object, {=0A= inspect: function(object) {=0A= try {=0A= if (object =3D=3D=3D undefined) return 'undefined';=0A= if (object =3D=3D=3D null) return 'null';=0A= return object.inspect ? object.inspect() : object.toString();=0A= } catch (e) {=0A= if (e instanceof RangeError) return '...';=0A= throw e;=0A= }=0A= },=0A= =0A= toJSON: function(object) {=0A= var type =3D typeof object;=0A= switch (type) {=0A= case 'undefined':=0A= case 'function':=0A= case 'unknown': return;=0A= case 'boolean': return object.toString();=0A= }=0A= =0A= if (object =3D=3D=3D null) return 'null';=0A= if (object.toJSON) return object.toJSON();=0A= if (Object.isElement(object)) return;=0A= =0A= var results =3D [];=0A= for (var property in object) {=0A= var value =3D Object.toJSON(object[property]);=0A= if (value !=3D=3D undefined)=0A= results.push(property.toJSON() + ': ' + value);=0A= }=0A= =0A= return '{' + results.join(', ') + '}';=0A= },=0A= =0A= toQueryString: function(object) {=0A= return $H(object).toQueryString();=0A= },=0A= =0A= toHTML: function(object) {=0A= return object && object.toHTML ? object.toHTML() : = String.interpret(object);=0A= },=0A= =0A= keys: function(object) {=0A= var keys =3D [];=0A= for (var property in object)=0A= keys.push(property);=0A= return keys;=0A= },=0A= =0A= values: function(object) {=0A= var values =3D [];=0A= for (var property in object)=0A= values.push(object[property]);=0A= return values;=0A= },=0A= =0A= clone: function(object) {=0A= return Object.extend({ }, object);=0A= },=0A= =0A= isElement: function(object) {=0A= return object && object.nodeType =3D=3D 1;=0A= },=0A= =0A= isArray: function(object) {=0A= return object && object.constructor =3D=3D=3D Array;=0A= },=0A= =0A= isHash: function(object) {=0A= return object instanceof Hash;=0A= },=0A= =0A= isFunction: function(object) {=0A= return typeof object =3D=3D "function";=0A= },=0A= =0A= isString: function(object) {=0A= return typeof object =3D=3D "string";=0A= },=0A= =0A= isNumber: function(object) {=0A= return typeof object =3D=3D "number";=0A= },=0A= =0A= isUndefined: function(object) {=0A= return typeof object =3D=3D "undefined";=0A= }=0A= });=0A= =0A= Object.extend(Function.prototype, {=0A= argumentNames: function() {=0A= var names =3D = this.toString().match(/^[\s$]*function[^(]*\((.*?)$/)[1].split(",").inv= oke("strip");=0A= return names.length =3D=3D 1 && !names[0] ? [] : names;=0A= },=0A= =0A= bind: function() {=0A= if (arguments.length < 2 && arguments[0] =3D=3D=3D undefined) return = this;=0A= var __method =3D this, args =3D $A(arguments), object =3D = args.shift();=0A= return function() {=0A= return __method.apply(object, args.concat($A(arguments)));=0A= }=0A= },=0A= =0A= bindAsEventListener: function() {=0A= var __method =3D this, args =3D $A(arguments), object =3D = args.shift();=0A= return function(event) {=0A= return __method.apply(object, [event || = window.event].concat(args));=0A= }=0A= },=0A= =0A= curry: function() {=0A= if (!arguments.length) return this;=0A= var __method =3D this, args =3D $A(arguments);=0A= return function() {=0A= return __method.apply(this, args.concat($A(arguments)));=0A= }=0A= },=0A= =0A= delay: function() {=0A= var __method =3D this, args =3D $A(arguments), timeout =3D = args.shift() * 1000;=0A= return window.setTimeout(function() {=0A= return __method.apply(__method, args);=0A= }, timeout);=0A= },=0A= =0A= wrap: function(wrapper) {=0A= var __method =3D this;=0A= return function() {=0A= return wrapper.apply(this, = [__method.bind(this)].concat($A(arguments)));=0A= }=0A= },=0A= =0A= methodize: function() {=0A= if (this._methodized) return this._methodized;=0A= var __method =3D this;=0A= return this._methodized =3D function() {=0A= return __method.apply(null, [this].concat($A(arguments)));=0A= };=0A= }=0A= });=0A= =0A= Function.prototype.defer =3D Function.prototype.delay.curry(0.01);=0A= =0A= Date.prototype.toJSON =3D function() {=0A= return '"' + this.getUTCFullYear() + '-' +=0A= (this.getUTCMonth() + 1).toPaddedString(2) + '-' +=0A= this.getUTCDate().toPaddedString(2) + 'T' +=0A= this.getUTCHours().toPaddedString(2) + ':' +=0A= this.getUTCMinutes().toPaddedString(2) + ':' +=0A= this.getUTCSeconds().toPaddedString(2) + 'Z"';=0A= };=0A= =0A= var Try =3D {=0A= these: function() {=0A= var returnValue;=0A= =0A= for (var i =3D 0, length =3D arguments.length; i < length; i++) {=0A= var lambda =3D arguments[i];=0A= try {=0A= returnValue =3D lambda();=0A= break;=0A= } catch (e) { }=0A= }=0A= =0A= return returnValue;=0A= }=0A= };=0A= =0A= RegExp.prototype.match =3D RegExp.prototype.test;=0A= =0A= RegExp.escape =3D function(str) {=0A= return String(str).replace(/([.*+?^=3D!:${}()|[\]\/\\])/g, '\\$1');=0A= };=0A= =0A= /*-----------------------------------------------------------------------= ---*/=0A= =0A= var PeriodicalExecuter =3D Class.create({=0A= initialize: function(callback, frequency) {=0A= this.callback =3D callback;=0A= this.frequency =3D frequency;=0A= this.currentlyExecuting =3D false;=0A= =0A= this.registerCallback();=0A= },=0A= =0A= registerCallback: function() {=0A= this.timer =3D setInterval(this.onTimerEvent.bind(this), = this.frequency * 1000);=0A= },=0A= =0A= execute: function() {=0A= this.callback(this);=0A= },=0A= =0A= stop: function() {=0A= if (!this.timer) return;=0A= clearInterval(this.timer);=0A= this.timer =3D null;=0A= },=0A= =0A= onTimerEvent: function() {=0A= if (!this.currentlyExecuting) {=0A= try {=0A= this.currentlyExecuting =3D true;=0A= this.execute();=0A= } finally {=0A= this.currentlyExecuting =3D false;=0A= }=0A= }=0A= }=0A= });=0A= Object.extend(String, {=0A= interpret: function(value) {=0A= return value =3D=3D null ? '' : String(value);=0A= },=0A= specialChar: {=0A= '\b': '\\b',=0A= '\t': '\\t',=0A= '\n': '\\n',=0A= '\f': '\\f',=0A= '\r': '\\r',=0A= '\\': '\\\\'=0A= }=0A= });=0A= =0A= Object.extend(String.prototype, {=0A= gsub: function(pattern, replacement) {=0A= var result =3D '', source =3D this, match;=0A= replacement =3D arguments.callee.prepareReplacement(replacement);=0A= =0A= while (source.length > 0) {=0A= if (match =3D source.match(pattern)) {=0A= result +=3D source.slice(0, match.index);=0A= result +=3D String.interpret(replacement(match));=0A= source =3D source.slice(match.index + match[0].length);=0A= } else {=0A= result +=3D source, source =3D '';=0A= }=0A= }=0A= return result;=0A= },=0A= =0A= sub: function(pattern, replacement, count) {=0A= replacement =3D this.gsub.prepareReplacement(replacement);=0A= count =3D count =3D=3D=3D undefined ? 1 : count;=0A= =0A= return this.gsub(pattern, function(match) {=0A= if (--count < 0) return match[0];=0A= return replacement(match);=0A= });=0A= },=0A= =0A= scan: function(pattern, iterator) {=0A= this.gsub(pattern, iterator);=0A= return String(this);=0A= },=0A= =0A= truncate: function(length, truncation) {=0A= length =3D length || 30;=0A= truncation =3D truncation =3D=3D=3D undefined ? '...' : truncation;=0A= return this.length > length ?=0A= this.slice(0, length - truncation.length) + truncation : = String(this);=0A= },=0A= =0A= strip: function() {=0A= return this.replace(/^\s+/, '').replace(/\s+$/, '');=0A= },=0A= =0A= stripTags: function() {=0A= return this.replace(/<\/?[^>]+>/gi, '');=0A= },=0A= =0A= stripScripts: function() {=0A= return this.replace(new RegExp(Prototype.ScriptFragment, 'img'), '');=0A= },=0A= =0A= extractScripts: function() {=0A= var matchAll =3D new RegExp(Prototype.ScriptFragment, 'img');=0A= var matchOne =3D new RegExp(Prototype.ScriptFragment, 'im');=0A= return (this.match(matchAll) || []).map(function(scriptTag) {=0A= return (scriptTag.match(matchOne) || ['', ''])[1];=0A= });=0A= },=0A= =0A= evalScripts: function() {=0A= return this.extractScripts().map(function(script) { return = eval(script) });=0A= },=0A= =0A= escapeHTML: function() {=0A= var self =3D arguments.callee;=0A= self.text.data =3D this;=0A= return self.div.innerHTML;=0A= },=0A= =0A= unescapeHTML: function() {=0A= var div =3D new Element('div');=0A= div.innerHTML =3D this.stripTags();=0A= return div.childNodes[0] ? (div.childNodes.length > 1 ?=0A= $A(div.childNodes).inject('', function(memo, node) { return = memo+node.nodeValue }) :=0A= div.childNodes[0].nodeValue) : '';=0A= },=0A= =0A= toQueryParams: function(separator) {=0A= var match =3D this.strip().match(/([^?#]*)(#.*)?$/);=0A= if (!match) return { };=0A= =0A= return match[1].split(separator || '&').inject({ }, function(hash, = pair) {=0A= if ((pair =3D pair.split('=3D'))[0]) {=0A= var key =3D decodeURIComponent(pair.shift());=0A= var value =3D pair.length > 1 ? pair.join('=3D') : pair[0];=0A= if (value !=3D undefined) value =3D decodeURIComponent(value);=0A= =0A= if (key in hash) {=0A= if (!Object.isArray(hash[key])) hash[key] =3D [hash[key]];=0A= hash[key].push(value);=0A= }=0A= else hash[key] =3D value;=0A= }=0A= return hash;=0A= });=0A= },=0A= =0A= toArray: function() {=0A= return this.split('');=0A= },=0A= =0A= succ: function() {=0A= return this.slice(0, this.length - 1) +=0A= String.fromCharCode(this.charCodeAt(this.length - 1) + 1);=0A= },=0A= =0A= times: function(count) {=0A= return count < 1 ? '' : new Array(count + 1).join(this);=0A= },=0A= =0A= camelize: function() {=0A= var parts =3D this.split('-'), len =3D parts.length;=0A= if (len =3D=3D 1) return parts[0];=0A= =0A= var camelized =3D this.charAt(0) =3D=3D '-'=0A= ? parts[0].charAt(0).toUpperCase() + parts[0].substring(1)=0A= : parts[0];=0A= =0A= for (var i =3D 1; i < len; i++)=0A= camelized +=3D parts[i].charAt(0).toUpperCase() + = parts[i].substring(1);=0A= =0A= return camelized;=0A= },=0A= =0A= capitalize: function() {=0A= return this.charAt(0).toUpperCase() + = this.substring(1).toLowerCase();=0A= },=0A= =0A= underscore: function() {=0A= return this.gsub(/::/, = '/').gsub(/([A-Z]+)([A-Z][a-z])/,'#{1}_#{2}').gsub(/([a-z\d])([A-Z])/,'#{= 1}_#{2}').gsub(/-/,'_').toLowerCase();=0A= },=0A= =0A= dasherize: function() {=0A= return this.gsub(/_/,'-');=0A= },=0A= =0A= inspect: function(useDoubleQuotes) {=0A= var escapedString =3D this.gsub(/[\x00-\x1f\\]/, function(match) {=0A= var character =3D String.specialChar[match[0]];=0A= return character ? character : '\\u00' + = match[0].charCodeAt().toPaddedString(2, 16);=0A= });=0A= if (useDoubleQuotes) return '"' + escapedString.replace(/"/g, '\\"') = + '"';=0A= return "'" + escapedString.replace(/'/g, '\\\'') + "'";=0A= },=0A= =0A= toJSON: function() {=0A= return this.inspect(true);=0A= },=0A= =0A= unfilterJSON: function(filter) {=0A= return this.sub(filter || Prototype.JSONFilter, '#{1}');=0A= },=0A= =0A= isJSON: function() {=0A= var str =3D this.replace(/\\./g, '@').replace(/"[^"\\\n\r]*"/g, '');=0A= return (/^[,:{}\[\]0-9.\-+Eaeflnr-u \n\r\t]*$/).test(str);=0A= },=0A= =0A= evalJSON: function(sanitize) {=0A= var json =3D this.unfilterJSON();=0A= try {=0A= if (!sanitize || json.isJSON()) return eval('(' + json + ')');=0A= } catch (e) { }=0A= throw new SyntaxError('Badly formed JSON string: ' + this.inspect());=0A= },=0A= =0A= include: function(pattern) {=0A= return this.indexOf(pattern) > -1;=0A= },=0A= =0A= startsWith: function(pattern) {=0A= return this.indexOf(pattern) =3D=3D=3D 0;=0A= },=0A= =0A= endsWith: function(pattern) {=0A= var d =3D this.length - pattern.length;=0A= return d >=3D 0 && this.lastIndexOf(pattern) =3D=3D=3D d;=0A= },=0A= =0A= empty: function() {=0A= return this =3D=3D '';=0A= },=0A= =0A= blank: function() {=0A= return /^\s*$/.test(this);=0A= },=0A= =0A= interpolate: function(object, pattern) {=0A= return new Template(this, pattern).evaluate(object);=0A= }=0A= });=0A= =0A= if (Prototype.Browser.WebKit || Prototype.Browser.IE) = Object.extend(String.prototype, {=0A= escapeHTML: function() {=0A= return = this.replace(/&/g,'&').replace(//g,'>');=0A= },=0A= unescapeHTML: function() {=0A= return = this.replace(/&/g,'&').replace(/</g,'<').replace(/>/g,'>');=0A= }=0A= });=0A= =0A= String.prototype.gsub.prepareReplacement =3D function(replacement) {=0A= if (Object.isFunction(replacement)) return replacement;=0A= var template =3D new Template(replacement);=0A= return function(match) { return template.evaluate(match) };=0A= };=0A= =0A= String.prototype.parseQuery =3D String.prototype.toQueryParams;=0A= =0A= Object.extend(String.prototype.escapeHTML, {=0A= div: document.createElement('div'),=0A= text: document.createTextNode('')=0A= });=0A= =0A= with (String.prototype.escapeHTML) div.appendChild(text);=0A= =0A= var Template =3D Class.create({=0A= initialize: function(template, pattern) {=0A= this.template =3D template.toString();=0A= this.pattern =3D pattern || Template.Pattern;=0A= },=0A= =0A= evaluate: function(object) {=0A= if (Object.isFunction(object.toTemplateReplacements))=0A= object =3D object.toTemplateReplacements();=0A= =0A= return this.template.gsub(this.pattern, function(match) {=0A= if (object =3D=3D null) return '';=0A= =0A= var before =3D match[1] || '';=0A= if (before =3D=3D '\\') return match[2];=0A= =0A= var ctx =3D object, expr =3D match[3];=0A= var pattern =3D /^([^.[]+|\[((?:.*?[^\\])?)\])(\.|\[|$)/, match = =3D pattern.exec(expr);=0A= if (match =3D=3D null) return before;=0A= =0A= while (match !=3D null) {=0A= var comp =3D match[1].startsWith('[') ? match[2].gsub('\\\\]', = ']') : match[1];=0A= ctx =3D ctx[comp];=0A= if (null =3D=3D ctx || '' =3D=3D match[3]) break;=0A= expr =3D expr.substring('[' =3D=3D match[3] ? match[1].length : = match[0].length);=0A= match =3D pattern.exec(expr);=0A= }=0A= =0A= return before + String.interpret(ctx);=0A= }.bind(this));=0A= }=0A= });=0A= Template.Pattern =3D /(^|.|\r|\n)(#\{(.*?)\})/;=0A= =0A= var $break =3D { };=0A= =0A= var Enumerable =3D {=0A= each: function(iterator, context) {=0A= var index =3D 0;=0A= iterator =3D iterator.bind(context);=0A= try {=0A= this._each(function(value) {=0A= iterator(value, index++);=0A= });=0A= } catch (e) {=0A= if (e !=3D $break) throw e;=0A= }=0A= return this;=0A= },=0A= =0A= eachSlice: function(number, iterator, context) {=0A= iterator =3D iterator ? iterator.bind(context) : Prototype.K;=0A= var index =3D -number, slices =3D [], array =3D this.toArray();=0A= while ((index +=3D number) < array.length)=0A= slices.push(array.slice(index, index+number));=0A= return slices.collect(iterator, context);=0A= },=0A= =0A= all: function(iterator, context) {=0A= iterator =3D iterator ? iterator.bind(context) : Prototype.K;=0A= var result =3D true;=0A= this.each(function(value, index) {=0A= result =3D result && !!iterator(value, index);=0A= if (!result) throw $break;=0A= });=0A= return result;=0A= },=0A= =0A= any: function(iterator, context) {=0A= iterator =3D iterator ? iterator.bind(context) : Prototype.K;=0A= var result =3D false;=0A= this.each(function(value, index) {=0A= if (result =3D !!iterator(value, index))=0A= throw $break;=0A= });=0A= return result;=0A= },=0A= =0A= collect: function(iterator, context) {=0A= iterator =3D iterator ? iterator.bind(context) : Prototype.K;=0A= var results =3D [];=0A= this.each(function(value, index) {=0A= results.push(iterator(value, index));=0A= });=0A= return results;=0A= },=0A= =0A= detect: function(iterator, context) {=0A= iterator =3D iterator.bind(context);=0A= var result;=0A= this.each(function(value, index) {=0A= if (iterator(value, index)) {=0A= result =3D value;=0A= throw $break;=0A= }=0A= });=0A= return result;=0A= },=0A= =0A= findAll: function(iterator, context) {=0A= iterator =3D iterator.bind(context);=0A= var results =3D [];=0A= this.each(function(value, index) {=0A= if (iterator(value, index))=0A= results.push(value);=0A= });=0A= return results;=0A= },=0A= =0A= grep: function(filter, iterator, context) {=0A= iterator =3D iterator ? iterator.bind(context) : Prototype.K;=0A= var results =3D [];=0A= =0A= if (Object.isString(filter))=0A= filter =3D new RegExp(filter);=0A= =0A= this.each(function(value, index) {=0A= if (filter.match(value))=0A= results.push(iterator(value, index));=0A= });=0A= return results;=0A= },=0A= =0A= include: function(object) {=0A= if (Object.isFunction(this.indexOf))=0A= if (this.indexOf(object) !=3D -1) return true;=0A= =0A= var found =3D false;=0A= this.each(function(value) {=0A= if (value =3D=3D object) {=0A= found =3D true;=0A= throw $break;=0A= }=0A= });=0A= return found;=0A= },=0A= =0A= inGroupsOf: function(number, fillWith) {=0A= fillWith =3D fillWith =3D=3D=3D undefined ? null : fillWith;=0A= return this.eachSlice(number, function(slice) {=0A= while(slice.length < number) slice.push(fillWith);=0A= return slice;=0A= });=0A= },=0A= =0A= inject: function(memo, iterator, context) {=0A= iterator =3D iterator.bind(context);=0A= this.each(function(value, index) {=0A= memo =3D iterator(memo, value, index);=0A= });=0A= return memo;=0A= },=0A= =0A= invoke: function(method) {=0A= var args =3D $A(arguments).slice(1);=0A= return this.map(function(value) {=0A= return value[method].apply(value, args);=0A= });=0A= },=0A= =0A= max: function(iterator, context) {=0A= iterator =3D iterator ? iterator.bind(context) : Prototype.K;=0A= var result;=0A= this.each(function(value, index) {=0A= value =3D iterator(value, index);=0A= if (result =3D=3D undefined || value >=3D result)=0A= result =3D value;=0A= });=0A= return result;=0A= },=0A= =0A= min: function(iterator, context) {=0A= iterator =3D iterator ? iterator.bind(context) : Prototype.K;=0A= var result;=0A= this.each(function(value, index) {=0A= value =3D iterator(value, index);=0A= if (result =3D=3D undefined || value < result)=0A= result =3D value;=0A= });=0A= return result;=0A= },=0A= =0A= partition: function(iterator, context) {=0A= iterator =3D iterator ? iterator.bind(context) : Prototype.K;=0A= var trues =3D [], falses =3D [];=0A= this.each(function(value, index) {=0A= (iterator(value, index) ?=0A= trues : falses).push(value);=0A= });=0A= return [trues, falses];=0A= },=0A= =0A= pluck: function(property) {=0A= var results =3D [];=0A= this.each(function(value) {=0A= results.push(value[property]);=0A= });=0A= return results;=0A= },=0A= =0A= reject: function(iterator, context) {=0A= iterator =3D iterator.bind(context);=0A= var results =3D [];=0A= this.each(function(value, index) {=0A= if (!iterator(value, index))=0A= results.push(value);=0A= });=0A= return results;=0A= },=0A= =0A= sortBy: function(iterator, context) {=0A= iterator =3D iterator.bind(context);=0A= return this.map(function(value, index) {=0A= return {value: value, criteria: iterator(value, index)};=0A= }).sort(function(left, right) {=0A= var a =3D left.criteria, b =3D right.criteria;=0A= return a < b ? -1 : a > b ? 1 : 0;=0A= }).pluck('value');=0A= },=0A= =0A= toArray: function() {=0A= return this.map();=0A= },=0A= =0A= zip: function() {=0A= var iterator =3D Prototype.K, args =3D $A(arguments);=0A= if (Object.isFunction(args.last()))=0A= iterator =3D args.pop();=0A= =0A= var collections =3D [this].concat(args).map($A);=0A= return this.map(function(value, index) {=0A= return iterator(collections.pluck(index));=0A= });=0A= },=0A= =0A= size: function() {=0A= return this.toArray().length;=0A= },=0A= =0A= inspect: function() {=0A= return '#';=0A= }=0A= };=0A= =0A= Object.extend(Enumerable, {=0A= map: Enumerable.collect,=0A= find: Enumerable.detect,=0A= select: Enumerable.findAll,=0A= filter: Enumerable.findAll,=0A= member: Enumerable.include,=0A= entries: Enumerable.toArray,=0A= every: Enumerable.all,=0A= some: Enumerable.any=0A= });=0A= function $A(iterable) {=0A= if (!iterable) return [];=0A= if (iterable.toArray) return iterable.toArray();=0A= var length =3D iterable.length, results =3D new Array(length);=0A= while (length--) results[length] =3D iterable[length];=0A= return results;=0A= }=0A= =0A= if (Prototype.Browser.WebKit) {=0A= function $A(iterable) {=0A= if (!iterable) return [];=0A= if (!(Object.isFunction(iterable) && iterable =3D=3D '[object = NodeList]') &&=0A= iterable.toArray) return iterable.toArray();=0A= var length =3D iterable.length, results =3D new Array(length);=0A= while (length--) results[length] =3D iterable[length];=0A= return results;=0A= }=0A= }=0A= =0A= Array.from =3D $A;=0A= =0A= Object.extend(Array.prototype, Enumerable);=0A= =0A= if (!Array.prototype._reverse) Array.prototype._reverse =3D = Array.prototype.reverse;=0A= =0A= Object.extend(Array.prototype, {=0A= _each: function(iterator) {=0A= for (var i =3D 0, length =3D this.length; i < length; i++)=0A= iterator(this[i]);=0A= },=0A= =0A= clear: function() {=0A= this.length =3D 0;=0A= return this;=0A= },=0A= =0A= first: function() {=0A= return this[0];=0A= },=0A= =0A= last: function() {=0A= return this[this.length - 1];=0A= },=0A= =0A= compact: function() {=0A= return this.select(function(value) {=0A= return value !=3D null;=0A= });=0A= },=0A= =0A= flatten: function() {=0A= return this.inject([], function(array, value) {=0A= return array.concat(Object.isArray(value) ?=0A= value.flatten() : [value]);=0A= });=0A= },=0A= =0A= without: function() {=0A= var values =3D $A(arguments);=0A= return this.select(function(value) {=0A= return !values.include(value);=0A= });=0A= },=0A= =0A= reverse: function(inline) {=0A= return (inline !=3D=3D false ? this : this.toArray())._reverse();=0A= },=0A= =0A= reduce: function() {=0A= return this.length > 1 ? this : this[0];=0A= },=0A= =0A= uniq: function(sorted) {=0A= return this.inject([], function(array, value, index) {=0A= if (0 =3D=3D index || (sorted ? array.last() !=3D value : = !array.include(value)))=0A= array.push(value);=0A= return array;=0A= });=0A= },=0A= =0A= intersect: function(array) {=0A= return this.uniq().findAll(function(item) {=0A= return array.detect(function(value) { return item =3D=3D=3D value = });=0A= });=0A= },=0A= =0A= clone: function() {=0A= return [].concat(this);=0A= },=0A= =0A= size: function() {=0A= return this.length;=0A= },=0A= =0A= inspect: function() {=0A= return '[' + this.map(Object.inspect).join(', ') + ']';=0A= },=0A= =0A= toJSON: function() {=0A= var results =3D [];=0A= this.each(function(object) {=0A= var value =3D Object.toJSON(object);=0A= if (value !=3D=3D undefined) results.push(value);=0A= });=0A= return '[' + results.join(', ') + ']';=0A= }=0A= });=0A= =0A= // use native browser JS 1.6 implementation if available=0A= if (Object.isFunction(Array.prototype.forEach))=0A= Array.prototype._each =3D Array.prototype.forEach;=0A= =0A= if (!Array.prototype.indexOf) Array.prototype.indexOf =3D function(item, = i) {=0A= i || (i =3D 0);=0A= var length =3D this.length;=0A= if (i < 0) i =3D length + i;=0A= for (; i < length; i++)=0A= if (this[i] =3D=3D=3D item) return i;=0A= return -1;=0A= };=0A= =0A= if (!Array.prototype.lastIndexOf) Array.prototype.lastIndexOf =3D = function(item, i) {=0A= i =3D isNaN(i) ? this.length : (i < 0 ? this.length + i : i) + 1;=0A= var n =3D this.slice(0, i).reverse().indexOf(item);=0A= return (n < 0) ? n : i - n - 1;=0A= };=0A= =0A= Array.prototype.toArray =3D Array.prototype.clone;=0A= =0A= function $w(string) {=0A= if (!Object.isString(string)) return [];=0A= string =3D string.strip();=0A= return string ? string.split(/\s+/) : [];=0A= }=0A= =0A= if (Prototype.Browser.Opera){=0A= Array.prototype.concat =3D function() {=0A= var array =3D [];=0A= for (var i =3D 0, length =3D this.length; i < length; i++) = array.push(this[i]);=0A= for (var i =3D 0, length =3D arguments.length; i < length; i++) {=0A= if (Object.isArray(arguments[i])) {=0A= for (var j =3D 0, arrayLength =3D arguments[i].length; j < = arrayLength; j++)=0A= array.push(arguments[i][j]);=0A= } else {=0A= array.push(arguments[i]);=0A= }=0A= }=0A= return array;=0A= };=0A= }=0A= Object.extend(Number.prototype, {=0A= toColorPart: function() {=0A= return this.toPaddedString(2, 16);=0A= },=0A= =0A= succ: function() {=0A= return this + 1;=0A= },=0A= =0A= times: function(iterator) {=0A= $R(0, this, true).each(iterator);=0A= return this;=0A= },=0A= =0A= toPaddedString: function(length, radix) {=0A= var string =3D this.toString(radix || 10);=0A= return '0'.times(length - string.length) + string;=0A= },=0A= =0A= toJSON: function() {=0A= return isFinite(this) ? this.toString() : 'null';=0A= }=0A= });=0A= =0A= $w('abs round ceil floor').each(function(method){=0A= Number.prototype[method] =3D Math[method].methodize();=0A= });=0A= function $H(object) {=0A= return new Hash(object);=0A= };=0A= =0A= var Hash =3D Class.create(Enumerable, (function() {=0A= if (function() {=0A= var i =3D 0, Test =3D function(value) { this.key =3D value };=0A= Test.prototype.key =3D 'foo';=0A= for (var property in new Test('bar')) i++;=0A= return i > 1;=0A= }()) {=0A= function each(iterator) {=0A= var cache =3D [];=0A= for (var key in this._object) {=0A= var value =3D this._object[key];=0A= if (cache.include(key)) continue;=0A= cache.push(key);=0A= var pair =3D [key, value];=0A= pair.key =3D key;=0A= pair.value =3D value;=0A= iterator(pair);=0A= }=0A= }=0A= } else {=0A= function each(iterator) {=0A= for (var key in this._object) {=0A= var value =3D this._object[key], pair =3D [key, value];=0A= pair.key =3D key;=0A= pair.value =3D value;=0A= iterator(pair);=0A= }=0A= }=0A= }=0A= =0A= function toQueryPair(key, value) {=0A= if (Object.isUndefined(value)) return key;=0A= return key + '=3D' + encodeURIComponent(String.interpret(value));=0A= }=0A= =0A= return {=0A= initialize: function(object) {=0A= this._object =3D Object.isHash(object) ? object.toObject() : = Object.clone(object);=0A= },=0A= =0A= _each: each,=0A= =0A= set: function(key, value) {=0A= return this._object[key] =3D value;=0A= },=0A= =0A= get: function(key) {=0A= return this._object[key];=0A= },=0A= =0A= unset: function(key) {=0A= var value =3D this._object[key];=0A= delete this._object[key];=0A= return value;=0A= },=0A= =0A= toObject: function() {=0A= return Object.clone(this._object);=0A= },=0A= =0A= keys: function() {=0A= return this.pluck('key');=0A= },=0A= =0A= values: function() {=0A= return this.pluck('value');=0A= },=0A= =0A= index: function(value) {=0A= var match =3D this.detect(function(pair) {=0A= return pair.value =3D=3D=3D value;=0A= });=0A= return match && match.key;=0A= },=0A= =0A= merge: function(object) {=0A= return this.clone().update(object);=0A= },=0A= =0A= update: function(object) {=0A= return new Hash(object).inject(this, function(result, pair) {=0A= result.set(pair.key, pair.value);=0A= return result;=0A= });=0A= },=0A= =0A= toQueryString: function() {=0A= return this.map(function(pair) {=0A= var key =3D encodeURIComponent(pair.key), values =3D pair.value;=0A= =0A= if (values && typeof values =3D=3D 'object') {=0A= if (Object.isArray(values))=0A= return values.map(toQueryPair.curry(key)).join('&');=0A= }=0A= return toQueryPair(key, values);=0A= }).join('&');=0A= },=0A= =0A= inspect: function() {=0A= return '#';=0A= },=0A= =0A= toJSON: function() {=0A= return Object.toJSON(this.toObject());=0A= },=0A= =0A= clone: function() {=0A= return new Hash(this);=0A= }=0A= }=0A= })());=0A= =0A= Hash.prototype.toTemplateReplacements =3D Hash.prototype.toObject;=0A= Hash.from =3D $H;=0A= var ObjectRange =3D Class.create(Enumerable, {=0A= initialize: function(start, end, exclusive) {=0A= this.start =3D start;=0A= this.end =3D end;=0A= this.exclusive =3D exclusive;=0A= },=0A= =0A= _each: function(iterator) {=0A= var value =3D this.start;=0A= while (this.include(value)) {=0A= iterator(value);=0A= value =3D value.succ();=0A= }=0A= },=0A= =0A= include: function(value) {=0A= if (value < this.start)=0A= return false;=0A= if (this.exclusive)=0A= return value < this.end;=0A= return value <=3D this.end;=0A= }=0A= });=0A= =0A= var $R =3D function(start, end, exclusive) {=0A= return new ObjectRange(start, end, exclusive);=0A= };=0A= =0A= var Ajax =3D {=0A= getTransport: function() {=0A= return Try.these(=0A= function() {return new XMLHttpRequest()},=0A= function() {return new ActiveXObject('Msxml2.XMLHTTP')},=0A= function() {return new ActiveXObject('Microsoft.XMLHTTP')}=0A= ) || false;=0A= },=0A= =0A= activeRequestCount: 0=0A= };=0A= =0A= Ajax.Responders =3D {=0A= responders: [],=0A= =0A= _each: function(iterator) {=0A= this.responders._each(iterator);=0A= },=0A= =0A= register: function(responder) {=0A= if (!this.include(responder))=0A= this.responders.push(responder);=0A= },=0A= =0A= unregister: function(responder) {=0A= this.responders =3D this.responders.without(responder);=0A= },=0A= =0A= dispatch: function(callback, request, transport, json) {=0A= this.each(function(responder) {=0A= if (Object.isFunction(responder[callback])) {=0A= try {=0A= responder[callback].apply(responder, [request, transport, = json]);=0A= } catch (e) { }=0A= }=0A= });=0A= }=0A= };=0A= =0A= Object.extend(Ajax.Responders, Enumerable);=0A= =0A= Ajax.Responders.register({=0A= onCreate: function() { Ajax.activeRequestCount++ },=0A= onComplete: function() { Ajax.activeRequestCount-- }=0A= });=0A= =0A= Ajax.Base =3D Class.create({=0A= initialize: function(options) {=0A= this.options =3D {=0A= method: 'post',=0A= asynchronous: true,=0A= contentType: 'application/x-www-form-urlencoded',=0A= encoding: 'UTF-8',=0A= parameters: '',=0A= evalJSON: true,=0A= evalJS: true=0A= };=0A= Object.extend(this.options, options || { });=0A= =0A= this.options.method =3D this.options.method.toLowerCase();=0A= if (Object.isString(this.options.parameters))=0A= this.options.parameters =3D = this.options.parameters.toQueryParams();=0A= }=0A= });=0A= =0A= Ajax.Request =3D Class.create(Ajax.Base, {=0A= _complete: false,=0A= =0A= initialize: function($super, url, options) {=0A= $super(options);=0A= this.transport =3D Ajax.getTransport();=0A= this.request(url);=0A= },=0A= =0A= request: function(url) {=0A= this.url =3D url;=0A= this.method =3D this.options.method;=0A= var params =3D Object.clone(this.options.parameters);=0A= =0A= if (!['get', 'post'].include(this.method)) {=0A= // simulate other verbs over post=0A= params['_method'] =3D this.method;=0A= this.method =3D 'post';=0A= }=0A= =0A= this.parameters =3D params;=0A= =0A= if (params =3D Object.toQueryString(params)) {=0A= // when GET, append parameters to URL=0A= if (this.method =3D=3D 'get')=0A= this.url +=3D (this.url.include('?') ? '&' : '?') + params;=0A= else if (/Konqueror|Safari|KHTML/.test(navigator.userAgent))=0A= params +=3D '&_=3D';=0A= }=0A= =0A= try {=0A= var response =3D new Ajax.Response(this);=0A= if (this.options.onCreate) this.options.onCreate(response);=0A= Ajax.Responders.dispatch('onCreate', this, response);=0A= =0A= this.transport.open(this.method.toUpperCase(), this.url,=0A= this.options.asynchronous);=0A= =0A= if (this.options.asynchronous) = this.respondToReadyState.bind(this).defer(1);=0A= =0A= this.transport.onreadystatechange =3D = this.onStateChange.bind(this);=0A= this.setRequestHeaders();=0A= =0A= this.body =3D this.method =3D=3D 'post' ? (this.options.postBody = || params) : null;=0A= this.transport.send(this.body);=0A= =0A= /* Force Firefox to handle ready state 4 for synchronous requests = */=0A= if (!this.options.asynchronous && this.transport.overrideMimeType)=0A= this.onStateChange();=0A= =0A= }=0A= catch (e) {=0A= this.dispatchException(e);=0A= }=0A= },=0A= =0A= onStateChange: function() {=0A= var readyState =3D this.transport.readyState;=0A= if (readyState > 1 && !((readyState =3D=3D 4) && this._complete))=0A= this.respondToReadyState(this.transport.readyState);=0A= },=0A= =0A= setRequestHeaders: function() {=0A= var headers =3D {=0A= 'X-Requested-With': 'XMLHttpRequest',=0A= 'X-Prototype-Version': Prototype.Version,=0A= 'Accept': 'text/javascript, text/html, application/xml, text/xml, = */*'=0A= };=0A= =0A= if (this.method =3D=3D 'post') {=0A= headers['Content-type'] =3D this.options.contentType +=0A= (this.options.encoding ? '; charset=3D' + this.options.encoding = : '');=0A= =0A= /* Force "Connection: close" for older Mozilla browsers to work=0A= * around a bug where XMLHttpRequest sends an incorrect=0A= * Content-length header. See Mozilla Bugzilla #246651.=0A= */=0A= if (this.transport.overrideMimeType &&=0A= (navigator.userAgent.match(/Gecko\/(\d{4})/) || [0,2005])[1] < = 2005)=0A= headers['Connection'] =3D 'close';=0A= }=0A= =0A= // user-defined headers=0A= if (typeof this.options.requestHeaders =3D=3D 'object') {=0A= var extras =3D this.options.requestHeaders;=0A= =0A= if (Object.isFunction(extras.push))=0A= for (var i =3D 0, length =3D extras.length; i < length; i +=3D 2)=0A= headers[extras[i]] =3D extras[i+1];=0A= else=0A= $H(extras).each(function(pair) { headers[pair.key] =3D = pair.value });=0A= }=0A= =0A= for (var name in headers)=0A= this.transport.setRequestHeader(name, headers[name]);=0A= },=0A= =0A= success: function() {=0A= var status =3D this.getStatus();=0A= return !status || (status >=3D 200 && status < 300);=0A= },=0A= =0A= getStatus: function() {=0A= try {=0A= return this.transport.status || 0;=0A= } catch (e) { return 0 }=0A= },=0A= =0A= respondToReadyState: function(readyState) {=0A= var state =3D Ajax.Request.Events[readyState], response =3D new = Ajax.Response(this);=0A= =0A= if (state =3D=3D 'Complete') {=0A= try {=0A= this._complete =3D true;=0A= (this.options['on' + response.status]=0A= || this.options['on' + (this.success() ? 'Success' : 'Failure')]=0A= || Prototype.emptyFunction)(response, response.headerJSON);=0A= } catch (e) {=0A= this.dispatchException(e);=0A= }=0A= =0A= var contentType =3D response.getHeader('Content-type');=0A= if (this.options.evalJS =3D=3D 'force'=0A= || (this.options.evalJS && contentType=0A= && = contentType.match(/^\s*(text|application)\/(x-)?(java|ecma)script(;.*)?\s= *$/i)))=0A= this.evalResponse();=0A= }=0A= =0A= try {=0A= (this.options['on' + state] || Prototype.emptyFunction)(response, = response.headerJSON);=0A= Ajax.Responders.dispatch('on' + state, this, response, = response.headerJSON);=0A= } catch (e) {=0A= this.dispatchException(e);=0A= }=0A= =0A= if (state =3D=3D 'Complete') {=0A= // avoid memory leak in MSIE: clean up=0A= this.transport.onreadystatechange =3D Prototype.emptyFunction;=0A= }=0A= },=0A= =0A= getHeader: function(name) {=0A= try {=0A= return this.transport.getResponseHeader(name);=0A= } catch (e) { return null }=0A= },=0A= =0A= evalResponse: function() {=0A= try {=0A= return eval((this.transport.responseText || '').unfilterJSON());=0A= } catch (e) {=0A= this.dispatchException(e);=0A= }=0A= },=0A= =0A= dispatchException: function(exception) {=0A= (this.options.onException || Prototype.emptyFunction)(this, = exception);=0A= Ajax.Responders.dispatch('onException', this, exception);=0A= }=0A= });=0A= =0A= Ajax.Request.Events =3D=0A= ['Uninitialized', 'Loading', 'Loaded', 'Interactive', 'Complete'];=0A= =0A= Ajax.Response =3D Class.create({=0A= initialize: function(request){=0A= this.request =3D request;=0A= var transport =3D this.transport =3D request.transport,=0A= readyState =3D this.readyState =3D transport.readyState;=0A= =0A= if((readyState > 2 && !Prototype.Browser.IE) || readyState =3D=3D 4) = {=0A= this.status =3D this.getStatus();=0A= this.statusText =3D this.getStatusText();=0A= this.responseText =3D String.interpret(transport.responseText);=0A= this.headerJSON =3D this._getHeaderJSON();=0A= }=0A= =0A= if(readyState =3D=3D 4) {=0A= var xml =3D transport.responseXML;=0A= this.responseXML =3D xml =3D=3D=3D undefined ? null : xml;=0A= this.responseJSON =3D this._getResponseJSON();=0A= }=0A= },=0A= =0A= status: 0,=0A= statusText: '',=0A= =0A= getStatus: Ajax.Request.prototype.getStatus,=0A= =0A= getStatusText: function() {=0A= try {=0A= return this.transport.statusText || '';=0A= } catch (e) { return '' }=0A= },=0A= =0A= getHeader: Ajax.Request.prototype.getHeader,=0A= =0A= getAllHeaders: function() {=0A= try {=0A= return this.getAllResponseHeaders();=0A= } catch (e) { return null }=0A= },=0A= =0A= getResponseHeader: function(name) {=0A= return this.transport.getResponseHeader(name);=0A= },=0A= =0A= getAllResponseHeaders: function() {=0A= return this.transport.getAllResponseHeaders();=0A= },=0A= =0A= _getHeaderJSON: function() {=0A= var json =3D this.getHeader('X-JSON');=0A= if (!json) return null;=0A= json =3D decodeURIComponent(escape(json));=0A= try {=0A= return json.evalJSON(this.request.options.sanitizeJSON);=0A= } catch (e) {=0A= this.request.dispatchException(e);=0A= }=0A= },=0A= =0A= _getResponseJSON: function() {=0A= var options =3D this.request.options;=0A= if (!options.evalJSON || (options.evalJSON !=3D 'force' &&=0A= !(this.getHeader('Content-type') || = '').include('application/json')))=0A= return null;=0A= try {=0A= return this.transport.responseText.evalJSON(options.sanitizeJSON);=0A= } catch (e) {=0A= this.request.dispatchException(e);=0A= }=0A= }=0A= });=0A= =0A= Ajax.Updater =3D Class.create(Ajax.Request, {=0A= initialize: function($super, container, url, options) {=0A= this.container =3D {=0A= success: (container.success || container),=0A= failure: (container.failure || (container.success ? null : = container))=0A= };=0A= =0A= options =3D options || { };=0A= var onComplete =3D options.onComplete;=0A= options.onComplete =3D (function(response, param) {=0A= this.updateContent(response.responseText);=0A= if (Object.isFunction(onComplete)) onComplete(response, param);=0A= }).bind(this);=0A= =0A= $super(url, options);=0A= },=0A= =0A= updateContent: function(responseText) {=0A= var receiver =3D this.container[this.success() ? 'success' : = 'failure'],=0A= options =3D this.options;=0A= =0A= if (!options.evalScripts) responseText =3D = responseText.stripScripts();=0A= =0A= if (receiver =3D $(receiver)) {=0A= if (options.insertion) {=0A= if (Object.isString(options.insertion)) {=0A= var insertion =3D { }; insertion[options.insertion] =3D = responseText;=0A= receiver.insert(insertion);=0A= }=0A= else options.insertion(receiver, responseText);=0A= }=0A= else receiver.update(responseText);=0A= }=0A= =0A= if (this.success()) {=0A= if (this.onComplete) this.onComplete.bind(this).defer();=0A= }=0A= }=0A= });=0A= =0A= Ajax.PeriodicalUpdater =3D Class.create(Ajax.Base, {=0A= initialize: function($super, container, url, options) {=0A= $super(options);=0A= this.onComplete =3D this.options.onComplete;=0A= =0A= this.frequency =3D (this.options.frequency || 2);=0A= this.decay =3D (this.options.decay || 1);=0A= =0A= this.updater =3D { };=0A= this.container =3D container;=0A= this.url =3D url;=0A= =0A= this.start();=0A= },=0A= =0A= start: function() {=0A= this.options.onComplete =3D this.updateComplete.bind(this);=0A= this.onTimerEvent();=0A= },=0A= =0A= stop: function() {=0A= this.updater.options.onComplete =3D undefined;=0A= clearTimeout(this.timer);=0A= (this.onComplete || Prototype.emptyFunction).apply(this, arguments);=0A= },=0A= =0A= updateComplete: function(response) {=0A= if (this.options.decay) {=0A= this.decay =3D (response.responseText =3D=3D this.lastText ?=0A= this.decay * this.options.decay : 1);=0A= =0A= this.lastText =3D response.responseText;=0A= }=0A= this.timer =3D this.onTimerEvent.bind(this).delay(this.decay * = this.frequency);=0A= },=0A= =0A= onTimerEvent: function() {=0A= this.updater =3D new Ajax.Updater(this.container, this.url, = this.options);=0A= }=0A= });=0A= function $(element) {=0A= if (arguments.length > 1) {=0A= for (var i =3D 0, elements =3D [], length =3D arguments.length; i < = length; i++)=0A= elements.push($(arguments[i]));=0A= return elements;=0A= }=0A= if (Object.isString(element))=0A= element =3D document.getElementById(element);=0A= return Element.extend(element);=0A= }=0A= =0A= if (Prototype.BrowserFeatures.XPath) {=0A= document._getElementsByXPath =3D function(expression, parentElement) {=0A= var results =3D [];=0A= var query =3D document.evaluate(expression, $(parentElement) || = document,=0A= null, XPathResult.ORDERED_NODE_SNAPSHOT_TYPE, null);=0A= for (var i =3D 0, length =3D query.snapshotLength; i < length; i++)=0A= results.push(Element.extend(query.snapshotItem(i)));=0A= return results;=0A= };=0A= }=0A= =0A= /*-----------------------------------------------------------------------= ---*/=0A= =0A= if (!window.Node) var Node =3D { };=0A= =0A= if (!Node.ELEMENT_NODE) {=0A= // DOM level 2 ECMAScript Language Binding=0A= Object.extend(Node, {=0A= ELEMENT_NODE: 1,=0A= ATTRIBUTE_NODE: 2,=0A= TEXT_NODE: 3,=0A= CDATA_SECTION_NODE: 4,=0A= ENTITY_REFERENCE_NODE: 5,=0A= ENTITY_NODE: 6,=0A= PROCESSING_INSTRUCTION_NODE: 7,=0A= COMMENT_NODE: 8,=0A= DOCUMENT_NODE: 9,=0A= DOCUMENT_TYPE_NODE: 10,=0A= DOCUMENT_FRAGMENT_NODE: 11,=0A= NOTATION_NODE: 12=0A= });=0A= }=0A= =0A= (function() {=0A= var element =3D this.Element;=0A= this.Element =3D function(tagName, attributes) {=0A= attributes =3D attributes || { };=0A= tagName =3D tagName.toLowerCase();=0A= var cache =3D Element.cache;=0A= if (Prototype.Browser.IE && attributes.name) {=0A= tagName =3D '<' + tagName + ' name=3D"' + attributes.name + '">';=0A= delete attributes.name;=0A= return Element.writeAttribute(document.createElement(tagName), = attributes);=0A= }=0A= if (!cache[tagName]) cache[tagName] =3D = Element.extend(document.createElement(tagName));=0A= return Element.writeAttribute(cache[tagName].cloneNode(false), = attributes);=0A= };=0A= Object.extend(this.Element, element || { });=0A= }).call(window);=0A= =0A= Element.cache =3D { };=0A= =0A= Element.Methods =3D {=0A= visible: function(element) {=0A= return $(element).style.display !=3D 'none';=0A= },=0A= =0A= toggle: function(element) {=0A= element =3D $(element);=0A= Element[Element.visible(element) ? 'hide' : 'show'](element);=0A= return element;=0A= },=0A= =0A= hide: function(element) {=0A= $(element).style.display =3D 'none';=0A= return element;=0A= },=0A= =0A= show: function(element) {=0A= $(element).style.display =3D '';=0A= return element;=0A= },=0A= =0A= remove: function(element) {=0A= element =3D $(element);=0A= element.parentNode.removeChild(element);=0A= return element;=0A= },=0A= =0A= update: function(element, content) {=0A= element =3D $(element);=0A= if (content && content.toElement) content =3D content.toElement();=0A= if (Object.isElement(content)) return = element.update().insert(content);=0A= content =3D Object.toHTML(content);=0A= element.innerHTML =3D content.stripScripts();=0A= content.evalScripts.bind(content).defer();=0A= return element;=0A= },=0A= =0A= replace: function(element, content) {=0A= element =3D $(element);=0A= if (content && content.toElement) content =3D content.toElement();=0A= else if (!Object.isElement(content)) {=0A= content =3D Object.toHTML(content);=0A= var range =3D element.ownerDocument.createRange();=0A= range.selectNode(element);=0A= content.evalScripts.bind(content).defer();=0A= content =3D range.createContextualFragment(content.stripScripts());=0A= }=0A= element.parentNode.replaceChild(content, element);=0A= return element;=0A= },=0A= =0A= insert: function(element, insertions) {=0A= element =3D $(element);=0A= =0A= if (Object.isString(insertions) || Object.isNumber(insertions) ||=0A= Object.isElement(insertions) || (insertions && = (insertions.toElement || insertions.toHTML)))=0A= insertions =3D {bottom:insertions};=0A= =0A= var content, t, range;=0A= =0A= for (position in insertions) {=0A= content =3D insertions[position];=0A= position =3D position.toLowerCase();=0A= t =3D Element._insertionTranslations[position];=0A= =0A= if (content && content.toElement) content =3D content.toElement();=0A= if (Object.isElement(content)) {=0A= t.insert(element, content);=0A= continue;=0A= }=0A= =0A= content =3D Object.toHTML(content);=0A= =0A= range =3D element.ownerDocument.createRange();=0A= t.initializeRange(element, range);=0A= t.insert(element, = range.createContextualFragment(content.stripScripts()));=0A= =0A= content.evalScripts.bind(content).defer();=0A= }=0A= =0A= return element;=0A= },=0A= =0A= wrap: function(element, wrapper, attributes) {=0A= element =3D $(element);=0A= if (Object.isElement(wrapper))=0A= $(wrapper).writeAttribute(attributes || { });=0A= else if (Object.isString(wrapper)) wrapper =3D new Element(wrapper, = attributes);=0A= else wrapper =3D new Element('div', wrapper);=0A= if (element.parentNode)=0A= element.parentNode.replaceChild(wrapper, element);=0A= wrapper.appendChild(element);=0A= return wrapper;=0A= },=0A= =0A= inspect: function(element) {=0A= element =3D $(element);=0A= var result =3D '<' + element.tagName.toLowerCase();=0A= $H({'id': 'id', 'className': 'class'}).each(function(pair) {=0A= var property =3D pair.first(), attribute =3D pair.last();=0A= var value =3D (element[property] || '').toString();=0A= if (value) result +=3D ' ' + attribute + '=3D' + = value.inspect(true);=0A= });=0A= return result + '>';=0A= },=0A= =0A= recursivelyCollect: function(element, property) {=0A= element =3D $(element);=0A= var elements =3D [];=0A= while (element =3D element[property])=0A= if (element.nodeType =3D=3D 1)=0A= elements.push(Element.extend(element));=0A= return elements;=0A= },=0A= =0A= ancestors: function(element) {=0A= return $(element).recursivelyCollect('parentNode');=0A= },=0A= =0A= descendants: function(element) {=0A= return $A($(element).getElementsByTagName('*')).each(Element.extend);=0A= },=0A= =0A= firstDescendant: function(element) {=0A= element =3D $(element).firstChild;=0A= while (element && element.nodeType !=3D 1) element =3D = element.nextSibling;=0A= return $(element);=0A= },=0A= =0A= immediateDescendants: function(element) {=0A= if (!(element =3D $(element).firstChild)) return [];=0A= while (element && element.nodeType !=3D 1) element =3D = element.nextSibling;=0A= if (element) return [element].concat($(element).nextSiblings());=0A= return [];=0A= },=0A= =0A= previousSiblings: function(element) {=0A= return $(element).recursivelyCollect('previousSibling');=0A= },=0A= =0A= nextSiblings: function(element) {=0A= return $(element).recursivelyCollect('nextSibling');=0A= },=0A= =0A= siblings: function(element) {=0A= element =3D $(element);=0A= return = element.previousSiblings().reverse().concat(element.nextSiblings());=0A= },=0A= =0A= match: function(element, selector) {=0A= if (Object.isString(selector))=0A= selector =3D new Selector(selector);=0A= return selector.match($(element));=0A= },=0A= =0A= up: function(element, expression, index) {=0A= element =3D $(element);=0A= if (arguments.length =3D=3D 1) return $(element.parentNode);=0A= var ancestors =3D element.ancestors();=0A= return expression ? Selector.findElement(ancestors, expression, = index) :=0A= ancestors[index || 0];=0A= },=0A= =0A= down: function(element, expression, index) {=0A= element =3D $(element);=0A= if (arguments.length =3D=3D 1) return element.firstDescendant();=0A= var descendants =3D element.descendants();=0A= return expression ? Selector.findElement(descendants, expression, = index) :=0A= descendants[index || 0];=0A= },=0A= =0A= previous: function(element, expression, index) {=0A= element =3D $(element);=0A= if (arguments.length =3D=3D 1) return = $(Selector.handlers.previousElementSibling(element));=0A= var previousSiblings =3D element.previousSiblings();=0A= return expression ? Selector.findElement(previousSiblings, = expression, index) :=0A= previousSiblings[index || 0];=0A= },=0A= =0A= next: function(element, expression, index) {=0A= element =3D $(element);=0A= if (arguments.length =3D=3D 1) return = $(Selector.handlers.nextElementSibling(element));=0A= var nextSiblings =3D element.nextSiblings();=0A= return expression ? Selector.findElement(nextSiblings, expression, = index) :=0A= nextSiblings[index || 0];=0A= },=0A= =0A= select: function() {=0A= var args =3D $A(arguments), element =3D $(args.shift());=0A= return Selector.findChildElements(element, args);=0A= },=0A= =0A= adjacent: function() {=0A= var args =3D $A(arguments), element =3D $(args.shift());=0A= return Selector.findChildElements(element.parentNode, = args).without(element);=0A= },=0A= =0A= identify: function(element) {=0A= element =3D $(element);=0A= var id =3D element.readAttribute('id'), self =3D arguments.callee;=0A= if (id) return id;=0A= do { id =3D 'anonymous_element_' + self.counter++ } while ($(id));=0A= element.writeAttribute('id', id);=0A= return id;=0A= },=0A= =0A= readAttribute: function(element, name) {=0A= element =3D $(element);=0A= if (Prototype.Browser.IE) {=0A= var t =3D Element._attributeTranslations.read;=0A= if (t.values[name]) return t.values[name](element, name);=0A= if (t.names[name]) name =3D t.names[name];=0A= if (name.include(':')) {=0A= return (!element.attributes || !element.attributes[name]) ? null = :=0A= element.attributes[name].value;=0A= }=0A= }=0A= return element.getAttribute(name);=0A= },=0A= =0A= writeAttribute: function(element, name, value) {=0A= element =3D $(element);=0A= var attributes =3D { }, t =3D Element._attributeTranslations.write;=0A= =0A= if (typeof name =3D=3D 'object') attributes =3D name;=0A= else attributes[name] =3D value =3D=3D=3D undefined ? true : value;=0A= =0A= for (var attr in attributes) {=0A= var name =3D t.names[attr] || attr, value =3D attributes[attr];=0A= if (t.values[attr]) name =3D t.values[attr](element, value);=0A= if (value =3D=3D=3D false || value =3D=3D=3D null)=0A= element.removeAttribute(name);=0A= else if (value =3D=3D=3D true)=0A= element.setAttribute(name, name);=0A= else element.setAttribute(name, value);=0A= }=0A= return element;=0A= },=0A= =0A= getHeight: function(element) {=0A= return $(element).getDimensions().height;=0A= },=0A= =0A= getWidth: function(element) {=0A= return $(element).getDimensions().width;=0A= },=0A= =0A= classNames: function(element) {=0A= return new Element.ClassNames(element);=0A= },=0A= =0A= hasClassName: function(element, className) {=0A= if (!(element =3D $(element))) return;=0A= var elementClassName =3D element.className;=0A= return (elementClassName.length > 0 && (elementClassName =3D=3D = className ||=0A= new RegExp("(^|\\s)" + className + = "(\\s|$)").test(elementClassName)));=0A= },=0A= =0A= addClassName: function(element, className) {=0A= if (!(element =3D $(element))) return;=0A= if (!element.hasClassName(className))=0A= element.className +=3D (element.className ? ' ' : '') + className;=0A= return element;=0A= },=0A= =0A= removeClassName: function(element, className) {=0A= if (!(element =3D $(element))) return;=0A= element.className =3D element.className.replace(=0A= new RegExp("(^|\\s+)" + className + "(\\s+|$)"), ' ').strip();=0A= return element;=0A= },=0A= =0A= toggleClassName: function(element, className) {=0A= if (!(element =3D $(element))) return;=0A= return element[element.hasClassName(className) ?=0A= 'removeClassName' : 'addClassName'](className);=0A= },=0A= =0A= // removes whitespace-only text node children=0A= cleanWhitespace: function(element) {=0A= element =3D $(element);=0A= var node =3D element.firstChild;=0A= while (node) {=0A= var nextNode =3D node.nextSibling;=0A= if (node.nodeType =3D=3D 3 && !/\S/.test(node.nodeValue))=0A= element.removeChild(node);=0A= node =3D nextNode;=0A= }=0A= return element;=0A= },=0A= =0A= empty: function(element) {=0A= return $(element).innerHTML.blank();=0A= },=0A= =0A= descendantOf: function(element, ancestor) {=0A= element =3D $(element), ancestor =3D $(ancestor);=0A= =0A= if (element.compareDocumentPosition)=0A= return (element.compareDocumentPosition(ancestor) & 8) =3D=3D=3D 8;=0A= =0A= if (element.sourceIndex && !Prototype.Browser.Opera) {=0A= var e =3D element.sourceIndex, a =3D ancestor.sourceIndex,=0A= nextAncestor =3D ancestor.nextSibling;=0A= if (!nextAncestor) {=0A= do { ancestor =3D ancestor.parentNode; }=0A= while (!(nextAncestor =3D ancestor.nextSibling) && = ancestor.parentNode);=0A= }=0A= if (nextAncestor) return (e > a && e < nextAncestor.sourceIndex);=0A= }=0A= =0A= while (element =3D element.parentNode)=0A= if (element =3D=3D ancestor) return true;=0A= return false;=0A= },=0A= =0A= scrollTo: function(element) {=0A= element =3D $(element);=0A= var pos =3D element.cumulativeOffset();=0A= window.scrollTo(pos[0], pos[1]);=0A= return element;=0A= },=0A= =0A= getStyle: function(element, style) {=0A= element =3D $(element);=0A= style =3D style =3D=3D 'float' ? 'cssFloat' : style.camelize();=0A= var value =3D element.style[style];=0A= if (!value) {=0A= var css =3D document.defaultView.getComputedStyle(element, null);=0A= value =3D css ? css[style] : null;=0A= }=0A= if (style =3D=3D 'opacity') return value ? parseFloat(value) : 1.0;=0A= return value =3D=3D 'auto' ? null : value;=0A= },=0A= =0A= getOpacity: function(element) {=0A= return $(element).getStyle('opacity');=0A= },=0A= =0A= setStyle: function(element, styles) {=0A= element =3D $(element);=0A= var elementStyle =3D element.style, match;=0A= if (Object.isString(styles)) {=0A= element.style.cssText +=3D ';' + styles;=0A= return styles.include('opacity') ?=0A= element.setOpacity(styles.match(/opacity:\s*(\d?\.?\d*)/)[1]) : = element;=0A= }=0A= for (var property in styles)=0A= if (property =3D=3D 'opacity') = element.setOpacity(styles[property]);=0A= else=0A= elementStyle[(property =3D=3D 'float' || property =3D=3D = 'cssFloat') ?=0A= (elementStyle.styleFloat =3D=3D=3D undefined ? 'cssFloat' : = 'styleFloat') :=0A= property] =3D styles[property];=0A= =0A= return element;=0A= },=0A= =0A= setOpacity: function(element, value) {=0A= element =3D $(element);=0A= element.style.opacity =3D (value =3D=3D 1 || value =3D=3D=3D '') ? = '' :=0A= (value < 0.00001) ? 0 : value;=0A= return element;=0A= },=0A= =0A= getDimensions: function(element) {=0A= element =3D $(element);=0A= var display =3D $(element).getStyle('display');=0A= if (display !=3D 'none' && display !=3D null) // Safari bug=0A= return {width: element.offsetWidth, height: element.offsetHeight};=0A= =0A= // All *Width and *Height properties give 0 on elements with display = none,=0A= // so enable the element temporarily=0A= var els =3D element.style;=0A= var originalVisibility =3D els.visibility;=0A= var originalPosition =3D els.position;=0A= var originalDisplay =3D els.display;=0A= els.visibility =3D 'hidden';=0A= els.position =3D 'absolute';=0A= els.display =3D 'block';=0A= var originalWidth =3D element.clientWidth;=0A= var originalHeight =3D element.clientHeight;=0A= els.display =3D originalDisplay;=0A= els.position =3D originalPosition;=0A= els.visibility =3D originalVisibility;=0A= return {width: originalWidth, height: originalHeight};=0A= },=0A= =0A= makePositioned: function(element) {=0A= element =3D $(element);=0A= var pos =3D Element.getStyle(element, 'position');=0A= if (pos =3D=3D 'static' || !pos) {=0A= element._madePositioned =3D true;=0A= element.style.position =3D 'relative';=0A= // Opera returns the offset relative to the positioning context, = when an=0A= // element is position relative but top and left have not been = defined=0A= if (window.opera) {=0A= element.style.top =3D 0;=0A= element.style.left =3D 0;=0A= }=0A= }=0A= return element;=0A= },=0A= =0A= undoPositioned: function(element) {=0A= element =3D $(element);=0A= if (element._madePositioned) {=0A= element._madePositioned =3D undefined;=0A= element.style.position =3D=0A= element.style.top =3D=0A= element.style.left =3D=0A= element.style.bottom =3D=0A= element.style.right =3D '';=0A= }=0A= return element;=0A= },=0A= =0A= makeClipping: function(element) {=0A= element =3D $(element);=0A= if (element._overflow) return element;=0A= element._overflow =3D Element.getStyle(element, 'overflow') || = 'auto';=0A= if (element._overflow !=3D=3D 'hidden')=0A= element.style.overflow =3D 'hidden';=0A= return element;=0A= },=0A= =0A= undoClipping: function(element) {=0A= element =3D $(element);=0A= if (!element._overflow) return element;=0A= element.style.overflow =3D element._overflow =3D=3D 'auto' ? '' : = element._overflow;=0A= element._overflow =3D null;=0A= return element;=0A= },=0A= =0A= cumulativeOffset: function(element) {=0A= var valueT =3D 0, valueL =3D 0;=0A= do {=0A= valueT +=3D element.offsetTop || 0;=0A= valueL +=3D element.offsetLeft || 0;=0A= element =3D element.offsetParent;=0A= } while (element);=0A= return Element._returnOffset(valueL, valueT);=0A= },=0A= =0A= positionedOffset: function(element) {=0A= var valueT =3D 0, valueL =3D 0;=0A= do {=0A= valueT +=3D element.offsetTop || 0;=0A= valueL +=3D element.offsetLeft || 0;=0A= element =3D element.offsetParent;=0A= if (element) {=0A= if (element.tagName =3D=3D 'BODY') break;=0A= var p =3D Element.getStyle(element, 'position');=0A= if (p =3D=3D 'relative' || p =3D=3D 'absolute') break;=0A= }=0A= } while (element);=0A= return Element._returnOffset(valueL, valueT);=0A= },=0A= =0A= absolutize: function(element) {=0A= element =3D $(element);=0A= if (element.getStyle('position') =3D=3D 'absolute') return;=0A= // Position.prepare(); // To be done manually by Scripty when it = needs it.=0A= =0A= var offsets =3D element.positionedOffset();=0A= var top =3D offsets[1];=0A= var left =3D offsets[0];=0A= var width =3D element.clientWidth;=0A= var height =3D element.clientHeight;=0A= =0A= element._originalLeft =3D left - parseFloat(element.style.left || = 0);=0A= element._originalTop =3D top - parseFloat(element.style.top || = 0);=0A= element._originalWidth =3D element.style.width;=0A= element._originalHeight =3D element.style.height;=0A= =0A= element.style.position =3D 'absolute';=0A= element.style.top =3D top + 'px';=0A= element.style.left =3D left + 'px';=0A= element.style.width =3D width + 'px';=0A= element.style.height =3D height + 'px';=0A= return element;=0A= },=0A= =0A= relativize: function(element) {=0A= element =3D $(element);=0A= if (element.getStyle('position') =3D=3D 'relative') return;=0A= // Position.prepare(); // To be done manually by Scripty when it = needs it.=0A= =0A= element.style.position =3D 'relative';=0A= var top =3D parseFloat(element.style.top || 0) - = (element._originalTop || 0);=0A= var left =3D parseFloat(element.style.left || 0) - = (element._originalLeft || 0);=0A= =0A= element.style.top =3D top + 'px';=0A= element.style.left =3D left + 'px';=0A= element.style.height =3D element._originalHeight;=0A= element.style.width =3D element._originalWidth;=0A= return element;=0A= },=0A= =0A= cumulativeScrollOffset: function(element) {=0A= var valueT =3D 0, valueL =3D 0;=0A= do {=0A= valueT +=3D element.scrollTop || 0;=0A= valueL +=3D element.scrollLeft || 0;=0A= element =3D element.parentNode;=0A= } while (element);=0A= return Element._returnOffset(valueL, valueT);=0A= },=0A= =0A= getOffsetParent: function(element) {=0A= if (element.offsetParent) return $(element.offsetParent);=0A= if (element =3D=3D document.body) return $(element);=0A= =0A= while ((element =3D element.parentNode) && element !=3D = document.body)=0A= if (Element.getStyle(element, 'position') !=3D 'static')=0A= return $(element);=0A= =0A= return $(document.body);=0A= },=0A= =0A= viewportOffset: function(forElement) {=0A= var valueT =3D 0, valueL =3D 0;=0A= =0A= var element =3D forElement;=0A= do {=0A= valueT +=3D element.offsetTop || 0;=0A= valueL +=3D element.offsetLeft || 0;=0A= =0A= // Safari fix=0A= if (element.offsetParent =3D=3D document.body &&=0A= Element.getStyle(element, 'position') =3D=3D 'absolute') break;=0A= =0A= } while (element =3D element.offsetParent);=0A= =0A= element =3D forElement;=0A= do {=0A= if (!Prototype.Browser.Opera || element.tagName =3D=3D 'BODY') {=0A= valueT -=3D element.scrollTop || 0;=0A= valueL -=3D element.scrollLeft || 0;=0A= }=0A= } while (element =3D element.parentNode);=0A= =0A= return Element._returnOffset(valueL, valueT);=0A= },=0A= =0A= clonePosition: function(element, source) {=0A= var options =3D Object.extend({=0A= setLeft: true,=0A= setTop: true,=0A= setWidth: true,=0A= setHeight: true,=0A= offsetTop: 0,=0A= offsetLeft: 0=0A= }, arguments[2] || { });=0A= =0A= // find page position of source=0A= source =3D $(source);=0A= var p =3D source.viewportOffset();=0A= =0A= // find coordinate system to use=0A= element =3D $(element);=0A= var delta =3D [0, 0];=0A= var parent =3D null;=0A= // delta [0,0] will do fine with position: fixed elements,=0A= // position:absolute needs offsetParent deltas=0A= if (Element.getStyle(element, 'position') =3D=3D 'absolute') {=0A= parent =3D element.getOffsetParent();=0A= delta =3D parent.viewportOffset();=0A= }=0A= =0A= // correct by body offsets (fixes Safari)=0A= if (parent =3D=3D document.body) {=0A= delta[0] -=3D document.body.offsetLeft;=0A= delta[1] -=3D document.body.offsetTop;=0A= }=0A= =0A= // set position=0A= if (options.setLeft) element.style.left =3D (p[0] - delta[0] + = options.offsetLeft) + 'px';=0A= if (options.setTop) element.style.top =3D (p[1] - delta[1] + = options.offsetTop) + 'px';=0A= if (options.setWidth) element.style.width =3D source.offsetWidth + = 'px';=0A= if (options.setHeight) element.style.height =3D source.offsetHeight = + 'px';=0A= return element;=0A= }=0A= };=0A= =0A= Element.Methods.identify.counter =3D 1;=0A= =0A= Object.extend(Element.Methods, {=0A= getElementsBySelector: Element.Methods.select,=0A= childElements: Element.Methods.immediateDescendants=0A= });=0A= =0A= Element._attributeTranslations =3D {=0A= write: {=0A= names: {=0A= className: 'class',=0A= htmlFor: 'for'=0A= },=0A= values: { }=0A= }=0A= };=0A= =0A= =0A= if (!document.createRange || Prototype.Browser.Opera) {=0A= Element.Methods.insert =3D function(element, insertions) {=0A= element =3D $(element);=0A= =0A= if (Object.isString(insertions) || Object.isNumber(insertions) ||=0A= Object.isElement(insertions) || (insertions && = (insertions.toElement || insertions.toHTML)))=0A= insertions =3D { bottom: insertions };=0A= =0A= var t =3D Element._insertionTranslations, content, position, pos, = tagName;=0A= =0A= for (position in insertions) {=0A= content =3D insertions[position];=0A= position =3D position.toLowerCase();=0A= pos =3D t[position];=0A= =0A= if (content && content.toElement) content =3D content.toElement();=0A= if (Object.isElement(content)) {=0A= pos.insert(element, content);=0A= continue;=0A= }=0A= =0A= content =3D Object.toHTML(content);=0A= tagName =3D ((position =3D=3D 'before' || position =3D=3D 'after')=0A= ? element.parentNode : element).tagName.toUpperCase();=0A= =0A= if (t.tags[tagName]) {=0A= var fragments =3D = Element._getContentFromAnonymousElement(tagName, content.stripScripts());=0A= if (position =3D=3D 'top' || position =3D=3D 'after') = fragments.reverse();=0A= fragments.each(pos.insert.curry(element));=0A= }=0A= else element.insertAdjacentHTML(pos.adjacency, = content.stripScripts());=0A= =0A= content.evalScripts.bind(content).defer();=0A= }=0A= =0A= return element;=0A= };=0A= }=0A= =0A= if (Prototype.Browser.Opera) {=0A= Element.Methods._getStyle =3D Element.Methods.getStyle;=0A= Element.Methods.getStyle =3D function(element, style) {=0A= switch(style) {=0A= case 'left':=0A= case 'top':=0A= case 'right':=0A= case 'bottom':=0A= if (Element._getStyle(element, 'position') =3D=3D 'static') = return null;=0A= default: return Element._getStyle(element, style);=0A= }=0A= };=0A= Element.Methods._readAttribute =3D Element.Methods.readAttribute;=0A= Element.Methods.readAttribute =3D function(element, attribute) {=0A= if (attribute =3D=3D 'title') return element.title;=0A= return Element._readAttribute(element, attribute);=0A= };=0A= }=0A= =0A= else if (Prototype.Browser.IE) {=0A= $w('positionedOffset getOffsetParent = viewportOffset').each(function(method) {=0A= Element.Methods[method] =3D Element.Methods[method].wrap(=0A= function(proceed, element) {=0A= element =3D $(element);=0A= var position =3D element.getStyle('position');=0A= if (position !=3D 'static') return proceed(element);=0A= element.setStyle({ position: 'relative' });=0A= var value =3D proceed(element);=0A= element.setStyle({ position: position });=0A= return value;=0A= }=0A= );=0A= });=0A= =0A= Element.Methods.getStyle =3D function(element, style) {=0A= element =3D $(element);=0A= style =3D (style =3D=3D 'float' || style =3D=3D 'cssFloat') ? = 'styleFloat' : style.camelize();=0A= var value =3D element.style[style];=0A= if (!value && element.currentStyle) value =3D = element.currentStyle[style];=0A= =0A= if (style =3D=3D 'opacity') {=0A= if (value =3D (element.getStyle('filter') || = '').match(/alpha$opacity=3D(.*)$/))=0A= if (value[1]) return parseFloat(value[1]) / 100;=0A= return 1.0;=0A= }=0A= =0A= if (value =3D=3D 'auto') {=0A= if ((style =3D=3D 'width' || style =3D=3D 'height') && = (element.getStyle('display') !=3D 'none'))=0A= return element['offset' + style.capitalize()] + 'px';=0A= return null;=0A= }=0A= return value;=0A= };=0A= =0A= Element.Methods.setOpacity =3D function(element, value) {=0A= function stripAlpha(filter){=0A= return filter.replace(/alpha$[^$]*\)/gi,'');=0A= }=0A= element =3D $(element);=0A= var currentStyle =3D element.currentStyle;=0A= if ((currentStyle && !currentStyle.hasLayout) ||=0A= (!currentStyle && element.style.zoom =3D=3D 'normal'))=0A= element.style.zoom =3D 1;=0A= =0A= var filter =3D element.getStyle('filter'), style =3D element.style;=0A= if (value =3D=3D 1 || value =3D=3D=3D '') {=0A= (filter =3D stripAlpha(filter)) ?=0A= style.filter =3D filter : style.removeAttribute('filter');=0A= return element;=0A= } else if (value < 0.00001) value =3D 0;=0A= style.filter =3D stripAlpha(filter) +=0A= 'alpha(opacity=3D' + (value * 100) + ')';=0A= return element;=0A= };=0A= =0A= Element._attributeTranslations =3D {=0A= read: {=0A= names: {=0A= 'class': 'className',=0A= 'for': 'htmlFor'=0A= },=0A= values: {=0A= _getAttr: function(element, attribute) {=0A= return element.getAttribute(attribute, 2);=0A= },=0A= _getAttrNode: function(element, attribute) {=0A= var node =3D element.getAttributeNode(attribute);=0A= return node ? node.value : "";=0A= },=0A= _getEv: function(element, attribute) {=0A= var attribute =3D element.getAttribute(attribute);=0A= return attribute ? attribute.toString().slice(23, -2) : null;=0A= },=0A= _flag: function(element, attribute) {=0A= return $(element).hasAttribute(attribute) ? attribute : null;=0A= },=0A= style: function(element) {=0A= return element.style.cssText.toLowerCase();=0A= },=0A= title: function(element) {=0A= return element.title;=0A= }=0A= }=0A= }=0A= };=0A= =0A= Element._attributeTranslations.write =3D {=0A= names: Object.clone(Element._attributeTranslations.read.names),=0A= values: {=0A= checked: function(element, value) {=0A= element.checked =3D !!value;=0A= },=0A= =0A= style: function(element, value) {=0A= element.style.cssText =3D value ? value : '';=0A= }=0A= }=0A= };=0A= =0A= Element._attributeTranslations.has =3D {};=0A= =0A= $w('colSpan rowSpan vAlign dateTime accessKey tabIndex ' +=0A= 'encType maxLength readOnly longDesc').each(function(attr) {=0A= Element._attributeTranslations.write.names[attr.toLowerCase()] =3D = attr;=0A= Element._attributeTranslations.has[attr.toLowerCase()] =3D attr;=0A= });=0A= =0A= (function(v) {=0A= Object.extend(v, {=0A= href: v._getAttr,=0A= src: v._getAttr,=0A= type: v._getAttr,=0A= action: v._getAttrNode,=0A= disabled: v._flag,=0A= checked: v._flag,=0A= readonly: v._flag,=0A= multiple: v._flag,=0A= onload: v._getEv,=0A= onunload: v._getEv,=0A= onclick: v._getEv,=0A= ondblclick: v._getEv,=0A= onmousedown: v._getEv,=0A= onmouseup: v._getEv,=0A= onmouseover: v._getEv,=0A= onmousemove: v._getEv,=0A= onmouseout: v._getEv,=0A= onfocus: v._getEv,=0A= onblur: v._getEv,=0A= onkeypress: v._getEv,=0A= onkeydown: v._getEv,=0A= onkeyup: v._getEv,=0A= onsubmit: v._getEv,=0A= onreset: v._getEv,=0A= onselect: v._getEv,=0A= onchange: v._getEv=0A= });=0A= })(Element._attributeTranslations.read.values);=0A= }=0A= =0A= else if (Prototype.Browser.Gecko && = /rv:1\.8\.0/.test(navigator.userAgent)) {=0A= Element.Methods.setOpacity =3D function(element, value) {=0A= element =3D $(element);=0A= element.style.opacity =3D (value =3D=3D 1) ? 0.999999 :=0A= (value =3D=3D=3D '') ? '' : (value < 0.00001) ? 0 : value;=0A= return element;=0A= };=0A= }=0A= =0A= else if (Prototype.Browser.WebKit) {=0A= Element.Methods.setOpacity =3D function(element, value) {=0A= element =3D $(element);=0A= element.style.opacity =3D (value =3D=3D 1 || value =3D=3D=3D '') ? = '' :=0A= (value < 0.00001) ? 0 : value;=0A= =0A= if (value =3D=3D 1)=0A= if(element.tagName =3D=3D 'IMG' && element.width) {=0A= element.width++; element.width--;=0A= } else try {=0A= var n =3D document.createTextNode(' ');=0A= element.appendChild(n);=0A= element.removeChild(n);=0A= } catch (e) { }=0A= =0A= return element;=0A= };=0A= =0A= // Safari returns margins on body which is incorrect if the child is = absolutely=0A= // positioned. For performance reasons, redefine = Position.cumulativeOffset for=0A= // KHTML/WebKit only.=0A= Element.Methods.cumulativeOffset =3D function(element) {=0A= var valueT =3D 0, valueL =3D 0;=0A= do {=0A= valueT +=3D element.offsetTop || 0;=0A= valueL +=3D element.offsetLeft || 0;=0A= if (element.offsetParent =3D=3D document.body)=0A= if (Element.getStyle(element, 'position') =3D=3D 'absolute') = break;=0A= =0A= element =3D element.offsetParent;=0A= } while (element);=0A= =0A= return Element._returnOffset(valueL, valueT);=0A= };=0A= }=0A= =0A= if (Prototype.Browser.IE || Prototype.Browser.Opera) {=0A= // IE and Opera are missing .innerHTML support for TABLE-related and = SELECT elements=0A= Element.Methods.update =3D function(element, content) {=0A= element =3D $(element);=0A= =0A= if (content && content.toElement) content =3D content.toElement();=0A= if (Object.isElement(content)) return = element.update().insert(content);=0A= =0A= content =3D Object.toHTML(content);=0A= var tagName =3D element.tagName.toUpperCase();=0A= =0A= if (tagName in Element._insertionTranslations.tags) {=0A= $A(element.childNodes).each(function(node) { = element.removeChild(node) });=0A= Element._getContentFromAnonymousElement(tagName, = content.stripScripts())=0A= .each(function(node) { element.appendChild(node) });=0A= }=0A= else element.innerHTML =3D content.stripScripts();=0A= =0A= content.evalScripts.bind(content).defer();=0A= return element;=0A= };=0A= }=0A= =0A= if (document.createElement('div').outerHTML) {=0A= Element.Methods.replace =3D function(element, content) {=0A= element =3D $(element);=0A= =0A= if (content && content.toElement) content =3D content.toElement();=0A= if (Object.isElement(content)) {=0A= element.parentNode.replaceChild(content, element);=0A= return element;=0A= }=0A= =0A= content =3D Object.toHTML(content);=0A= var parent =3D element.parentNode, tagName =3D = parent.tagName.toUpperCase();=0A= =0A= if (Element._insertionTranslations.tags[tagName]) {=0A= var nextSibling =3D element.next();=0A= var fragments =3D Element._getContentFromAnonymousElement(tagName, = content.stripScripts());=0A= parent.removeChild(element);=0A= if (nextSibling)=0A= fragments.each(function(node) { parent.insertBefore(node, = nextSibling) });=0A= else=0A= fragments.each(function(node) { parent.appendChild(node) });=0A= }=0A= else element.outerHTML =3D content.stripScripts();=0A= =0A= content.evalScripts.bind(content).defer();=0A= return element;=0A= };=0A= }=0A= =0A= Element._returnOffset =3D function(l, t) {=0A= var result =3D [l, t];=0A= result.left =3D l;=0A= result.top =3D t;=0A= return result;=0A= };=0A= =0A= Element._getContentFromAnonymousElement =3D function(tagName, html) {=0A= var div =3D new Element('div'), t =3D = Element._insertionTranslations.tags[tagName];=0A= div.innerHTML =3D t[0] + html + t[1];=0A= t[2].times(function() { div =3D div.firstChild });=0A= return $A(div.childNodes);=0A= };=0A= =0A= Element._insertionTranslations =3D {=0A= before: {=0A= adjacency: 'beforeBegin',=0A= insert: function(element, node) {=0A= element.parentNode.insertBefore(node, element);=0A= },=0A= initializeRange: function(element, range) {=0A= range.setStartBefore(element);=0A= }=0A= },=0A= top: {=0A= adjacency: 'afterBegin',=0A= insert: function(element, node) {=0A= element.insertBefore(node, element.firstChild);=0A= },=0A= initializeRange: function(element, range) {=0A= range.selectNodeContents(element);=0A= range.collapse(true);=0A= }=0A= },=0A= bottom: {=0A= adjacency: 'beforeEnd',=0A= insert: function(element, node) {=0A= element.appendChild(node);=0A= }=0A= },=0A= after: {=0A= adjacency: 'afterEnd',=0A= insert: function(element, node) {=0A= element.parentNode.insertBefore(node, element.nextSibling);=0A= },=0A= initializeRange: function(element, range) {=0A= range.setStartAfter(element);=0A= }=0A= },=0A= tags: {=0A= TABLE: ['

Custom Antibodies
Monoclonal & Polyclonal Antibodies Variety = of=20 Services and Species

www.svlab.com

', '
', 1],=0A= TBODY: ['', '
', 2],=0A= TR: ['', '
', 3],=0A= TD: ['
', '
', 4],=0A= SELECT: ['', 1]=0A= }=0A= };=0A= =0A= (function() {=0A= this.bottom.initializeRange =3D this.top.initializeRange;=0A= Object.extend(this.tags, {=0A= THEAD: this.tags.TBODY,=0A= TFOOT: this.tags.TBODY,=0A= TH: this.tags.TD=0A= });=0A= }).call(Element._insertionTranslations);=0A= =0A= Element.Methods.Simulated =3D {=0A= hasAttribute: function(element, attribute) {=0A= attribute =3D Element._attributeTranslations.has[attribute] || = attribute;=0A= var node =3D $(element).getAttributeNode(attribute);=0A= return node && node.specified;=0A= }=0A= };=0A= =0A= Element.Methods.ByTag =3D { };=0A= =0A= Object.extend(Element, Element.Methods);=0A= =0A= if (!Prototype.BrowserFeatures.ElementExtensions &&=0A= document.createElement('div').__proto__) {=0A= window.HTMLElement =3D { };=0A= window.HTMLElement.prototype =3D = document.createElement('div').__proto__;=0A= Prototype.BrowserFeatures.ElementExtensions =3D true;=0A= }=0A= =0A= Element.extend =3D (function() {=0A= if (Prototype.BrowserFeatures.SpecificElementExtensions)=0A= return Prototype.K;=0A= =0A= var Methods =3D { }, ByTag =3D Element.Methods.ByTag;=0A= =0A= var extend =3D Object.extend(function(element) {=0A= if (!element || element._extendedByPrototype ||=0A= element.nodeType !=3D 1 || element =3D=3D window) return element;=0A= =0A= var methods =3D Object.clone(Methods),=0A= tagName =3D element.tagName, property, value;=0A= =0A= // extend methods for specific tags=0A= if (ByTag[tagName]) Object.extend(methods, ByTag[tagName]);=0A= =0A= for (property in methods) {=0A= value =3D methods[property];=0A= if (Object.isFunction(value) && !(property in element))=0A= element[property] =3D value.methodize();=0A= }=0A= =0A= element._extendedByPrototype =3D Prototype.emptyFunction;=0A= return element;=0A= =0A= }, {=0A= refresh: function() {=0A= // extend methods for all tags (Safari doesn't need this)=0A= if (!Prototype.BrowserFeatures.ElementExtensions) {=0A= Object.extend(Methods, Element.Methods);=0A= Object.extend(Methods, Element.Methods.Simulated);=0A= }=0A= }=0A= });=0A= =0A= extend.refresh();=0A= return extend;=0A= })();=0A= =0A= Element.hasAttribute =3D function(element, attribute) {=0A= if (element.hasAttribute) return element.hasAttribute(attribute);=0A= return Element.Methods.Simulated.hasAttribute(element, attribute);=0A= };=0A= =0A= Element.addMethods =3D function(methods) {=0A= var F =3D Prototype.BrowserFeatures, T =3D Element.Methods.ByTag;=0A= =0A= if (!methods) {=0A= Object.extend(Form, Form.Methods);=0A= Object.extend(Form.Element, Form.Element.Methods);=0A= Object.extend(Element.Methods.ByTag, {=0A= "FORM": Object.clone(Form.Methods),=0A= "INPUT": Object.clone(Form.Element.Methods),=0A= "SELECT": Object.clone(Form.Element.Methods),=0A= "TEXTAREA": Object.clone(Form.Element.Methods)=0A= });=0A= }=0A= =0A= if (arguments.length =3D=3D 2) {=0A= var tagName =3D methods;=0A= methods =3D arguments[1];=0A= }=0A= =0A= if (!tagName) Object.extend(Element.Methods, methods || { });=0A= else {=0A= if (Object.isArray(tagName)) tagName.each(extend);=0A= else extend(tagName);=0A= }=0A= =0A= function extend(tagName) {=0A= tagName =3D tagName.toUpperCase();=0A= if (!Element.Methods.ByTag[tagName])=0A= Element.Methods.ByTag[tagName] =3D { };=0A= Object.extend(Element.Methods.ByTag[tagName], methods);=0A= }=0A= =0A= function copy(methods, destination, onlyIfAbsent) {=0A= onlyIfAbsent =3D onlyIfAbsent || false;=0A= for (var property in methods) {=0A= var value =3D methods[property];=0A= if (!Object.isFunction(value)) continue;=0A= if (!onlyIfAbsent || !(property in destination))=0A= destination[property] =3D value.methodize();=0A= }=0A= }=0A= =0A= function findDOMClass(tagName) {=0A= var klass;=0A= var trans =3D {=0A= "OPTGROUP": "OptGroup", "TEXTAREA": "TextArea", "P": "Paragraph",=0A= "FIELDSET": "FieldSet", "UL": "UList", "OL": "OList", "DL": = "DList",=0A= "DIR": "Directory", "H1": "Heading", "H2": "Heading", "H3": = "Heading",=0A= "H4": "Heading", "H5": "Heading", "H6": "Heading", "Q": "Quote",=0A= "INS": "Mod", "DEL": "Mod", "A": "Anchor", "IMG": "Image", = "CAPTION":=0A= "TableCaption", "COL": "TableCol", "COLGROUP": "TableCol", "THEAD":=0A= "TableSection", "TFOOT": "TableSection", "TBODY": "TableSection", = "TR":=0A= "TableRow", "TH": "TableCell", "TD": "TableCell", "FRAMESET":=0A= "FrameSet", "IFRAME": "IFrame"=0A= };=0A= if (trans[tagName]) klass =3D 'HTML' + trans[tagName] + 'Element';=0A= if (window[klass]) return window[klass];=0A= klass =3D 'HTML' + tagName + 'Element';=0A= if (window[klass]) return window[klass];=0A= klass =3D 'HTML' + tagName.capitalize() + 'Element';=0A= if (window[klass]) return window[klass];=0A= =0A= window[klass] =3D { };=0A= window[klass].prototype =3D = document.createElement(tagName).__proto__;=0A= return window[klass];=0A= }=0A= =0A= if (F.ElementExtensions) {=0A= copy(Element.Methods, HTMLElement.prototype);=0A= copy(Element.Methods.Simulated, HTMLElement.prototype, true);=0A= }=0A= =0A= if (F.SpecificElementExtensions) {=0A= for (var tag in Element.Methods.ByTag) {=0A= var klass =3D findDOMClass(tag);=0A= if (Object.isUndefined(klass)) continue;=0A= copy(T[tag], klass.prototype);=0A= }=0A= }=0A= =0A= Object.extend(Element, Element.Methods);=0A= delete Element.ByTag;=0A= =0A= if (Element.extend.refresh) Element.extend.refresh();=0A= Element.cache =3D { };=0A= };=0A= =0A= document.viewport =3D {=0A= getDimensions: function() {=0A= var dimensions =3D { };=0A= $w('width height').each(function(d) {=0A= var D =3D d.capitalize();=0A= dimensions[d] =3D self['inner' + D] ||=0A= (document.documentElement['client' + D] || document.body['client' = + D]);=0A= });=0A= return dimensions;=0A= },=0A= =0A= getWidth: function() {=0A= return this.getDimensions().width;=0A= },=0A= =0A= getHeight: function() {=0A= return this.getDimensions().height;=0A= },=0A= =0A= getScrollOffsets: function() {=0A= return Element._returnOffset(=0A= window.pageXOffset || document.documentElement.scrollLeft || = document.body.scrollLeft,=0A= window.pageYOffset || document.documentElement.scrollTop || = document.body.scrollTop);=0A= }=0A= };=0A= /* Portions of the Selector class are derived from Jack = Slocum=C3=A2=E2=82=AC=E2=84=A2s DomQuery,=0A= * part of YUI-Ext version 0.40, distributed under the terms of an = MIT-style=0A= * license. Please see http://www.yui-ext.com/ for more information. */=0A= =0A= var Selector =3D Class.create({=0A= initialize: function(expression) {=0A= this.expression =3D expression.strip();=0A= this.compileMatcher();=0A= },=0A= =0A= compileMatcher: function() {=0A= // Selectors with namespaced attributes can't use the XPath version=0A= if (Prototype.BrowserFeatures.XPath && = !(/(\[[\w-]*?:|:checked)/).test(this.expression))=0A= return this.compileXPathMatcher();=0A= =0A= var e =3D this.expression, ps =3D Selector.patterns, h =3D = Selector.handlers,=0A= c =3D Selector.criteria, le, p, m;=0A= =0A= if (Selector._cache[e]) {=0A= this.matcher =3D Selector._cache[e];=0A= return;=0A= }=0A= =0A= this.matcher =3D ["this.matcher =3D function(root) {",=0A= "var r =3D root, h =3D Selector.handlers, c =3D = false, n;"];=0A= =0A= while (e && le !=3D e && (/\S/).test(e)) {=0A= le =3D e;=0A= for (var i in ps) {=0A= p =3D ps[i];=0A= if (m =3D e.match(p)) {=0A= this.matcher.push(Object.isFunction(c[i]) ? c[i](m) :=0A= new Template(c[i]).evaluate(m));=0A= e =3D e.replace(m[0], '');=0A= break;=0A= }=0A= }=0A= }=0A= =0A= this.matcher.push("return h.unique(n);\n}");=0A= eval(this.matcher.join('\n'));=0A= Selector._cache[this.expression] =3D this.matcher;=0A= },=0A= =0A= compileXPathMatcher: function() {=0A= var e =3D this.expression, ps =3D Selector.patterns,=0A= x =3D Selector.xpath, le, m;=0A= =0A= if (Selector._cache[e]) {=0A= this.xpath =3D Selector._cache[e]; return;=0A= }=0A= =0A= this.matcher =3D ['.//*'];=0A= while (e && le !=3D e && (/\S/).test(e)) {=0A= le =3D e;=0A= for (var i in ps) {=0A= if (m =3D e.match(ps[i])) {=0A= this.matcher.push(Object.isFunction(x[i]) ? x[i](m) :=0A= new Template(x[i]).evaluate(m));=0A= e =3D e.replace(m[0], '');=0A= break;=0A= }=0A= }=0A= }=0A= =0A= this.xpath =3D this.matcher.join('');=0A= Selector._cache[this.expression] =3D this.xpath;=0A= },=0A= =0A= findElements: function(root) {=0A= root =3D root || document;=0A= if (this.xpath) return document._getElementsByXPath(this.xpath, = root);=0A= return this.matcher(root);=0A= },=0A= =0A= match: function(element) {=0A= this.tokens =3D [];=0A= =0A= var e =3D this.expression, ps =3D Selector.patterns, as =3D = Selector.assertions;=0A= var le, p, m;=0A= =0A= while (e && le !=3D=3D e && (/\S/).test(e)) {=0A= le =3D e;=0A= for (var i in ps) {=0A= p =3D ps[i];=0A= if (m =3D e.match(p)) {=0A= // use the Selector.assertions methods unless the selector=0A= // is too complex.=0A= if (as[i]) {=0A= this.tokens.push([i, Object.clone(m)]);=0A= e =3D e.replace(m[0], '');=0A= } else {=0A= // reluctantly do a document-wide search=0A= // and look for a match in the array=0A= return this.findElements(document).include(element);=0A= }=0A= }=0A= }=0A= }=0A= =0A= var match =3D true, name, matches;=0A= for (var i =3D 0, token; token =3D this.tokens[i]; i++) {=0A= name =3D token[0], matches =3D token[1];=0A= if (!Selector.assertions[name](element, matches)) {=0A= match =3D false; break;=0A= }=0A= }=0A= =0A= return match;=0A= },=0A= =0A= toString: function() {=0A= return this.expression;=0A= },=0A= =0A= inspect: function() {=0A= return "#";=0A= }=0A= });=0A= =0A= Object.extend(Selector, {=0A= _cache: { },=0A= =0A= xpath: {=0A= descendant: "//*",=0A= child: "/*",=0A= adjacent: "/following-sibling::*[1]",=0A= laterSibling: '/following-sibling::*',=0A= tagName: function(m) {=0A= if (m[1] =3D=3D '*') return '';=0A= return "[local-name()=3D'" + m[1].toLowerCase() +=0A= "' or local-name()=3D'" + m[1].toUpperCase() + "']";=0A= },=0A= className: "[contains(concat(' ', @class, ' '), ' #{1} ')]",=0A= id: "[@id=3D'#{1}']",=0A= attrPresence: "[@#{1}]",=0A= attr: function(m) {=0A= m[3] =3D m[5] || m[6];=0A= return new Template(Selector.xpath.operators[m[2]]).evaluate(m);=0A= },=0A= pseudo: function(m) {=0A= var h =3D Selector.xpath.pseudos[m[1]];=0A= if (!h) return '';=0A= if (Object.isFunction(h)) return h(m);=0A= return new Template(Selector.xpath.pseudos[m[1]]).evaluate(m);=0A= },=0A= operators: {=0A= '=3D': "[@#{1}=3D'#{3}']",=0A= '!=3D': "[@#{1}!=3D'#{3}']",=0A= '^=3D': "[starts-with(@#{1}, '#{3}')]",=0A= '$=3D': "[substring(@#{1}, (string-length(@#{1}) - = string-length('#{3}') + 1))=3D'#{3}']",=0A= '*=3D': "[contains(@#{1}, '#{3}')]",=0A= '~=3D': "[contains(concat(' ', @#{1}, ' '), ' #{3} ')]",=0A= '|=3D': "[contains(concat('-', @#{1}, '-'), '-#{3}-')]"=0A= },=0A= pseudos: {=0A= 'first-child': '[not(preceding-sibling::*)]',=0A= 'last-child': '[not(following-sibling::*)]',=0A= 'only-child': '[not(preceding-sibling::* or = following-sibling::*)]',=0A= 'empty': "[count(*) =3D 0 and (count(text()) =3D 0 or = translate(text(), ' \t\r\n', '') =3D '')]",=0A= 'checked': "[@checked]",=0A= 'disabled': "[@disabled]",=0A= 'enabled': "[not(@disabled)]",=0A= 'not': function(m) {=0A= var e =3D m[6], p =3D Selector.patterns,=0A= x =3D Selector.xpath, le, m, v;=0A= =0A= var exclusion =3D [];=0A= while (e && le !=3D e && (/\S/).test(e)) {=0A= le =3D e;=0A= for (var i in p) {=0A= if (m =3D e.match(p[i])) {=0A= v =3D Object.isFunction(x[i]) ? x[i](m) : new = Template(x[i]).evaluate(m);=0A= exclusion.push("(" + v.substring(1, v.length - 1) + ")");=0A= e =3D e.replace(m[0], '');=0A= break;=0A= }=0A= }=0A= }=0A= return "[not(" + exclusion.join(" and ") + ")]";=0A= },=0A= 'nth-child': function(m) {=0A= return = Selector.xpath.pseudos.nth("(count(./preceding-sibling::*) + 1) ", m);=0A= },=0A= 'nth-last-child': function(m) {=0A= return = Selector.xpath.pseudos.nth("(count(./following-sibling::*) + 1) ", m);=0A= },=0A= 'nth-of-type': function(m) {=0A= return Selector.xpath.pseudos.nth("position() ", m);=0A= },=0A= 'nth-last-of-type': function(m) {=0A= return Selector.xpath.pseudos.nth("(last() + 1 - position()) ", = m);=0A= },=0A= 'first-of-type': function(m) {=0A= m[6] =3D "1"; return Selector.xpath.pseudos['nth-of-type'](m);=0A= },=0A= 'last-of-type': function(m) {=0A= m[6] =3D "1"; return = Selector.xpath.pseudos['nth-last-of-type'](m);=0A= },=0A= 'only-of-type': function(m) {=0A= var p =3D Selector.xpath.pseudos; return p['first-of-type'](m) + = p['last-of-type'](m);=0A= },=0A= nth: function(fragment, m) {=0A= var mm, formula =3D m[6], predicate;=0A= if (formula =3D=3D 'even') formula =3D '2n+0';=0A= if (formula =3D=3D 'odd') formula =3D '2n+1';=0A= if (mm =3D formula.match(/^(\d+)$/)) // digit only=0A= return '[' + fragment + "=3D " + mm[1] + ']';=0A= if (mm =3D formula.match(/^(-?\d*)?n(([+-])(\d+))?/)) { // an+b=0A= if (mm[1] =3D=3D "-") mm[1] =3D -1;=0A= var a =3D mm[1] ? Number(mm[1]) : 1;=0A= var b =3D mm[2] ? Number(mm[2]) : 0;=0A= predicate =3D "[((#{fragment} - #{b}) mod #{a} =3D 0) and " +=0A= "((#{fragment} - #{b}) div #{a} >=3D 0)]";=0A= return new Template(predicate).evaluate({=0A= fragment: fragment, a: a, b: b });=0A= }=0A= }=0A= }=0A= },=0A= =0A= criteria: {=0A= tagName: 'n =3D h.tagName(n, r, "#{1}", c); c =3D false;',=0A= className: 'n =3D h.className(n, r, "#{1}", c); c =3D false;',=0A= id: 'n =3D h.id(n, r, "#{1}", c); c =3D false;',=0A= attrPresence: 'n =3D h.attrPresence(n, r, "#{1}"); c =3D false;',=0A= attr: function(m) {=0A= m[3] =3D (m[5] || m[6]);=0A= return new Template('n =3D h.attr(n, r, "#{1}", "#{3}", "#{2}"); c = =3D false;').evaluate(m);=0A= },=0A= pseudo: function(m) {=0A= if (m[6]) m[6] =3D m[6].replace(/"/g, '\\"');=0A= return new Template('n =3D h.pseudo(n, "#{1}", "#{6}", r, c); c = =3D false;').evaluate(m);=0A= },=0A= descendant: 'c =3D "descendant";',=0A= child: 'c =3D "child";',=0A= adjacent: 'c =3D "adjacent";',=0A= laterSibling: 'c =3D "laterSibling";'=0A= },=0A= =0A= patterns: {=0A= // combinators must be listed first=0A= // (and descendant needs to be last combinator)=0A= laterSibling: /^\s*~\s*/,=0A= child: /^\s*>\s*/,=0A= adjacent: /^\s*\+\s*/,=0A= descendant: /^\s/,=0A= =0A= // selectors follow=0A= tagName: /^\s*(\*|[\w\-]+)(\b|$)?/,=0A= id: /^#([\w\-\*]+)(\b|$)/,=0A= className: /^\.([\w\-\*]+)(\b|$)/,=0A= pseudo: = /^:((first|last|nth|nth-last|only)(-child|-of-type)|empty|checked|(en|dis= )abled|not)($(.*?)$)?(\b|$|(?=3D\s)|(?=3D:))/,=0A= attrPresence: /^\[([\w]+)\]/,=0A= attr: = /\[((?:[\w-]*:)?[\w-]+)\s*(?:([!^$*~|]?=3D)\s*((['"])([^\4]*?)\4|([^'"][^= \]]*?)))?\]/=0A= },=0A= =0A= // for Selector.match and Element#match=0A= assertions: {=0A= tagName: function(element, matches) {=0A= return matches[1].toUpperCase() =3D=3D = element.tagName.toUpperCase();=0A= },=0A= =0A= className: function(element, matches) {=0A= return Element.hasClassName(element, matches[1]);=0A= },=0A= =0A= id: function(element, matches) {=0A= return element.id =3D=3D=3D matches[1];=0A= },=0A= =0A= attrPresence: function(element, matches) {=0A= return Element.hasAttribute(element, matches[1]);=0A= },=0A= =0A= attr: function(element, matches) {=0A= var nodeValue =3D Element.readAttribute(element, matches[1]);=0A= return Selector.operators[matches[2]](nodeValue, matches[3]);=0A= }=0A= },=0A= =0A= handlers: {=0A= // UTILITY FUNCTIONS=0A= // joins two collections=0A= concat: function(a, b) {=0A= for (var i =3D 0, node; node =3D b[i]; i++)=0A= a.push(node);=0A= return a;=0A= },=0A= =0A= // marks an array of nodes for counting=0A= mark: function(nodes) {=0A= for (var i =3D 0, node; node =3D nodes[i]; i++)=0A= node._counted =3D true;=0A= return nodes;=0A= },=0A= =0A= unmark: function(nodes) {=0A= for (var i =3D 0, node; node =3D nodes[i]; i++)=0A= node._counted =3D undefined;=0A= return nodes;=0A= },=0A= =0A= // mark each child node with its position (for nth calls)=0A= // "ofType" flag indicates whether we're indexing for nth-of-type=0A= // rather than nth-child=0A= index: function(parentNode, reverse, ofType) {=0A= parentNode._counted =3D true;=0A= if (reverse) {=0A= for (var nodes =3D parentNode.childNodes, i =3D nodes.length - = 1, j =3D 1; i >=3D 0; i--) {=0A= var node =3D nodes[i];=0A= if (node.nodeType =3D=3D 1 && (!ofType || node._counted)) = node.nodeIndex =3D j++;=0A= }=0A= } else {=0A= for (var i =3D 0, j =3D 1, nodes =3D parentNode.childNodes; node = =3D nodes[i]; i++)=0A= if (node.nodeType =3D=3D 1 && (!ofType || node._counted)) = node.nodeIndex =3D j++;=0A= }=0A= },=0A= =0A= // filters out duplicates and extends all nodes=0A= unique: function(nodes) {=0A= if (nodes.length =3D=3D 0) return nodes;=0A= var results =3D [], n;=0A= for (var i =3D 0, l =3D nodes.length; i < l; i++)=0A= if (!(n =3D nodes[i])._counted) {=0A= n._counted =3D true;=0A= results.push(Element.extend(n));=0A= }=0A= return Selector.handlers.unmark(results);=0A= },=0A= =0A= // COMBINATOR FUNCTIONS=0A= descendant: function(nodes) {=0A= var h =3D Selector.handlers;=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++)=0A= h.concat(results, node.getElementsByTagName('*'));=0A= return results;=0A= },=0A= =0A= child: function(nodes) {=0A= var h =3D Selector.handlers;=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++) {=0A= for (var j =3D 0, children =3D [], child; child =3D = node.childNodes[j]; j++)=0A= if (child.nodeType =3D=3D 1 && child.tagName !=3D '!') = results.push(child);=0A= }=0A= return results;=0A= },=0A= =0A= adjacent: function(nodes) {=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++) {=0A= var next =3D this.nextElementSibling(node);=0A= if (next) results.push(next);=0A= }=0A= return results;=0A= },=0A= =0A= laterSibling: function(nodes) {=0A= var h =3D Selector.handlers;=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++)=0A= h.concat(results, Element.nextSiblings(node));=0A= return results;=0A= },=0A= =0A= nextElementSibling: function(node) {=0A= while (node =3D node.nextSibling)=0A= if (node.nodeType =3D=3D 1) return node;=0A= return null;=0A= },=0A= =0A= previousElementSibling: function(node) {=0A= while (node =3D node.previousSibling)=0A= if (node.nodeType =3D=3D 1) return node;=0A= return null;=0A= },=0A= =0A= // TOKEN FUNCTIONS=0A= tagName: function(nodes, root, tagName, combinator) {=0A= tagName =3D tagName.toUpperCase();=0A= var results =3D [], h =3D Selector.handlers;=0A= if (nodes) {=0A= if (combinator) {=0A= // fastlane for ordinary descendant combinators=0A= if (combinator =3D=3D "descendant") {=0A= for (var i =3D 0, node; node =3D nodes[i]; i++)=0A= h.concat(results, node.getElementsByTagName(tagName));=0A= return results;=0A= } else nodes =3D this[combinator](nodes);=0A= if (tagName =3D=3D "*") return nodes;=0A= }=0A= for (var i =3D 0, node; node =3D nodes[i]; i++)=0A= if (node.tagName.toUpperCase() =3D=3D tagName) = results.push(node);=0A= return results;=0A= } else return root.getElementsByTagName(tagName);=0A= },=0A= =0A= id: function(nodes, root, id, combinator) {=0A= var targetNode =3D $(id), h =3D Selector.handlers;=0A= if (!targetNode) return [];=0A= if (!nodes && root =3D=3D document) return [targetNode];=0A= if (nodes) {=0A= if (combinator) {=0A= if (combinator =3D=3D 'child') {=0A= for (var i =3D 0, node; node =3D nodes[i]; i++)=0A= if (targetNode.parentNode =3D=3D node) return [targetNode];=0A= } else if (combinator =3D=3D 'descendant') {=0A= for (var i =3D 0, node; node =3D nodes[i]; i++)=0A= if (Element.descendantOf(targetNode, node)) return = [targetNode];=0A= } else if (combinator =3D=3D 'adjacent') {=0A= for (var i =3D 0, node; node =3D nodes[i]; i++)=0A= if (Selector.handlers.previousElementSibling(targetNode) = =3D=3D node)=0A= return [targetNode];=0A= } else nodes =3D h[combinator](nodes);=0A= }=0A= for (var i =3D 0, node; node =3D nodes[i]; i++)=0A= if (node =3D=3D targetNode) return [targetNode];=0A= return [];=0A= }=0A= return (targetNode && Element.descendantOf(targetNode, root)) ? = [targetNode] : [];=0A= },=0A= =0A= className: function(nodes, root, className, combinator) {=0A= if (nodes && combinator) nodes =3D this[combinator](nodes);=0A= return Selector.handlers.byClassName(nodes, root, className);=0A= },=0A= =0A= byClassName: function(nodes, root, className) {=0A= if (!nodes) nodes =3D Selector.handlers.descendant([root]);=0A= var needle =3D ' ' + className + ' ';=0A= for (var i =3D 0, results =3D [], node, nodeClassName; node =3D = nodes[i]; i++) {=0A= nodeClassName =3D node.className;=0A= if (nodeClassName.length =3D=3D 0) continue;=0A= if (nodeClassName =3D=3D className || (' ' + nodeClassName + ' = ').include(needle))=0A= results.push(node);=0A= }=0A= return results;=0A= },=0A= =0A= attrPresence: function(nodes, root, attr) {=0A= if (!nodes) nodes =3D root.getElementsByTagName("*");=0A= var results =3D [];=0A= for (var i =3D 0, node; node =3D nodes[i]; i++)=0A= if (Element.hasAttribute(node, attr)) results.push(node);=0A= return results;=0A= },=0A= =0A= attr: function(nodes, root, attr, value, operator) {=0A= if (!nodes) nodes =3D root.getElementsByTagName("*");=0A= var handler =3D Selector.operators[operator], results =3D [];=0A= for (var i =3D 0, node; node =3D nodes[i]; i++) {=0A= var nodeValue =3D Element.readAttribute(node, attr);=0A= if (nodeValue =3D=3D=3D null) continue;=0A= if (handler(nodeValue, value)) results.push(node);=0A= }=0A= return results;=0A= },=0A= =0A= pseudo: function(nodes, name, value, root, combinator) {=0A= if (nodes && combinator) nodes =3D this[combinator](nodes);=0A= if (!nodes) nodes =3D root.getElementsByTagName("*");=0A= return Selector.pseudos[name](nodes, value, root);=0A= }=0A= },=0A= =0A= pseudos: {=0A= 'first-child': function(nodes, value, root) {=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++) {=0A= if (Selector.handlers.previousElementSibling(node)) continue;=0A= results.push(node);=0A= }=0A= return results;=0A= },=0A= 'last-child': function(nodes, value, root) {=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++) {=0A= if (Selector.handlers.nextElementSibling(node)) continue;=0A= results.push(node);=0A= }=0A= return results;=0A= },=0A= 'only-child': function(nodes, value, root) {=0A= var h =3D Selector.handlers;=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++)=0A= if (!h.previousElementSibling(node) && = !h.nextElementSibling(node))=0A= results.push(node);=0A= return results;=0A= },=0A= 'nth-child': function(nodes, formula, root) {=0A= return Selector.pseudos.nth(nodes, formula, root);=0A= },=0A= 'nth-last-child': function(nodes, formula, root) {=0A= return Selector.pseudos.nth(nodes, formula, root, true);=0A= },=0A= 'nth-of-type': function(nodes, formula, root) {=0A= return Selector.pseudos.nth(nodes, formula, root, false, true);=0A= },=0A= 'nth-last-of-type': function(nodes, formula, root) {=0A= return Selector.pseudos.nth(nodes, formula, root, true, true);=0A= },=0A= 'first-of-type': function(nodes, formula, root) {=0A= return Selector.pseudos.nth(nodes, "1", root, false, true);=0A= },=0A= 'last-of-type': function(nodes, formula, root) {=0A= return Selector.pseudos.nth(nodes, "1", root, true, true);=0A= },=0A= 'only-of-type': function(nodes, formula, root) {=0A= var p =3D Selector.pseudos;=0A= return p['last-of-type'](p['first-of-type'](nodes, formula, root), = formula, root);=0A= },=0A= =0A= // handles the an+b logic=0A= getIndices: function(a, b, total) {=0A= if (a =3D=3D 0) return b > 0 ? [b] : [];=0A= return $R(1, total).inject([], function(memo, i) {=0A= if (0 =3D=3D (i - b) % a && (i - b) / a >=3D 0) memo.push(i);=0A= return memo;=0A= });=0A= },=0A= =0A= // handles nth(-last)-child, nth(-last)-of-type, and = (first|last)-of-type=0A= nth: function(nodes, formula, root, reverse, ofType) {=0A= if (nodes.length =3D=3D 0) return [];=0A= if (formula =3D=3D 'even') formula =3D '2n+0';=0A= if (formula =3D=3D 'odd') formula =3D '2n+1';=0A= var h =3D Selector.handlers, results =3D [], indexed =3D [], m;=0A= h.mark(nodes);=0A= for (var i =3D 0, node; node =3D nodes[i]; i++) {=0A= if (!node.parentNode._counted) {=0A= h.index(node.parentNode, reverse, ofType);=0A= indexed.push(node.parentNode);=0A= }=0A= }=0A= if (formula.match(/^\d+$/)) { // just a number=0A= formula =3D Number(formula);=0A= for (var i =3D 0, node; node =3D nodes[i]; i++)=0A= if (node.nodeIndex =3D=3D formula) results.push(node);=0A= } else if (m =3D formula.match(/^(-?\d*)?n(([+-])(\d+))?/)) { // = an+b=0A= if (m[1] =3D=3D "-") m[1] =3D -1;=0A= var a =3D m[1] ? Number(m[1]) : 1;=0A= var b =3D m[2] ? Number(m[2]) : 0;=0A= var indices =3D Selector.pseudos.getIndices(a, b, nodes.length);=0A= for (var i =3D 0, node, l =3D indices.length; node =3D nodes[i]; = i++) {=0A= for (var j =3D 0; j < l; j++)=0A= if (node.nodeIndex =3D=3D indices[j]) results.push(node);=0A= }=0A= }=0A= h.unmark(nodes);=0A= h.unmark(indexed);=0A= return results;=0A= },=0A= =0A= 'empty': function(nodes, value, root) {=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++) {=0A= // IE treats comments as element nodes=0A= if (node.tagName =3D=3D '!' || (node.firstChild && = !node.innerHTML.match(/^\s*$/))) continue;=0A= results.push(node);=0A= }=0A= return results;=0A= },=0A= =0A= 'not': function(nodes, selector, root) {=0A= var h =3D Selector.handlers, selectorType, m;=0A= var exclusions =3D new Selector(selector).findElements(root);=0A= h.mark(exclusions);=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++)=0A= if (!node._counted) results.push(node);=0A= h.unmark(exclusions);=0A= return results;=0A= },=0A= =0A= 'enabled': function(nodes, value, root) {=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++)=0A= if (!node.disabled) results.push(node);=0A= return results;=0A= },=0A= =0A= 'disabled': function(nodes, value, root) {=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++)=0A= if (node.disabled) results.push(node);=0A= return results;=0A= },=0A= =0A= 'checked': function(nodes, value, root) {=0A= for (var i =3D 0, results =3D [], node; node =3D nodes[i]; i++)=0A= if (node.checked) results.push(node);=0A= return results;=0A= }=0A= },=0A= =0A= operators: {=0A= '=3D': function(nv, v) { return nv =3D=3D v; },=0A= '!=3D': function(nv, v) { return nv !=3D v; },=0A= '^=3D': function(nv, v) { return nv.startsWith(v); },=0A= '$=3D': function(nv, v) { return nv.endsWith(v); },=0A= '*=3D': function(nv, v) { return nv.include(v); },=0A= '~=3D': function(nv, v) { return (' ' + nv + ' ').include(' ' + v + = ' '); },=0A= '|=3D': function(nv, v) { return ('-' + nv.toUpperCase() + = '-').include('-' + v.toUpperCase() + '-'); }=0A= },=0A= =0A= matchElements: function(elements, expression) {=0A= var matches =3D new Selector(expression).findElements(), h =3D = Selector.handlers;=0A= h.mark(matches);=0A= for (var i =3D 0, results =3D [], element; element =3D elements[i]; = i++)=0A= if (element._counted) results.push(element);=0A= h.unmark(matches);=0A= return results;=0A= },=0A= =0A= findElement: function(elements, expression, index) {=0A= if (Object.isNumber(expression)) {=0A= index =3D expression; expression =3D false;=0A= }=0A= return Selector.matchElements(elements, expression || '*')[index || = 0];=0A= },=0A= =0A= findChildElements: function(element, expressions) {=0A= var exprs =3D expressions.join(','), expressions =3D [];=0A= exprs.scan(/(([\w#:.~>+()\s-]+|\*|\[.*?\])+)\s*(,|$)/, function(m) {=0A= expressions.push(m[1].strip());=0A= });=0A= var results =3D [], h =3D Selector.handlers;=0A= for (var i =3D 0, l =3D expressions.length, selector; i < l; i++) {=0A= selector =3D new Selector(expressions[i].strip());=0A= h.concat(results, selector.findElements(element));=0A= }=0A= return (l > 1) ? h.unique(results) : results;=0A= }=0A= });=0A= =0A= function $$() {=0A= return Selector.findChildElements(document, $A(arguments));=0A= }=0A= var Form =3D {=0A= reset: function(form) {=0A= $(form).reset();=0A= return form;=0A= },=0A= =0A= serializeElements: function(elements, options) {=0A= if (typeof options !=3D 'object') options =3D { hash: !!options };=0A= else if (options.hash =3D=3D=3D undefined) options.hash =3D true;=0A= var key, value, submitted =3D false, submit =3D options.submit;=0A= =0A= var data =3D elements.inject({ }, function(result, element) {=0A= if (!element.disabled && element.name) {=0A= key =3D element.name; value =3D $(element).getValue();=0A= if (value !=3D null && (element.type !=3D 'submit' || = (!submitted &&=0A= submit !=3D=3D false && (!submit || key =3D=3D submit) && = (submitted =3D true)))) {=0A= if (key in result) {=0A= // a key is already present; construct an array of values=0A= if (!Object.isArray(result[key])) result[key] =3D = [result[key]];=0A= result[key].push(value);=0A= }=0A= else result[key] =3D value;=0A= }=0A= }=0A= return result;=0A= });=0A= =0A= return options.hash ? data : Object.toQueryString(data);=0A= }=0A= };=0A= =0A= Form.Methods =3D {=0A= serialize: function(form, options) {=0A= return Form.serializeElements(Form.getElements(form), options);=0A= },=0A= =0A= getElements: function(form) {=0A= return $A($(form).getElementsByTagName('*')).inject([],=0A= function(elements, child) {=0A= if (Form.Element.Serializers[child.tagName.toLowerCase()])=0A= elements.push(Element.extend(child));=0A= return elements;=0A= }=0A= );=0A= },=0A= =0A= getInputs: function(form, typeName, name) {=0A= form =3D $(form);=0A= var inputs =3D form.getElementsByTagName('input');=0A= =0A= if (!typeName && !name) return $A(inputs).map(Element.extend);=0A= =0A= for (var i =3D 0, matchingInputs =3D [], length =3D inputs.length; i = < length; i++) {=0A= var input =3D inputs[i];=0A= if ((typeName && input.type !=3D typeName) || (name && input.name = !=3D name))=0A= continue;=0A= matchingInputs.push(Element.extend(input));=0A= }=0A= =0A= return matchingInputs;=0A= },=0A= =0A= disable: function(form) {=0A= form =3D $(form);=0A= Form.getElements(form).invoke('disable');=0A= return form;=0A= },=0A= =0A= enable: function(form) {=0A= form =3D $(form);=0A= Form.getElements(form).invoke('enable');=0A= return form;=0A= },=0A= =0A= findFirstElement: function(form) {=0A= var elements =3D $(form).getElements().findAll(function(element) {=0A= return 'hidden' !=3D element.type && !element.disabled;=0A= });=0A= var firstByIndex =3D elements.findAll(function(element) {=0A= return element.hasAttribute('tabIndex') && element.tabIndex >=3D 0;=0A= }).sortBy(function(element) { return element.tabIndex }).first();=0A= =0A= return firstByIndex ? firstByIndex : elements.find(function(element) = {=0A= return ['input', 'select', = 'textarea'].include(element.tagName.toLowerCase());=0A= });=0A= },=0A= =0A= focusFirstElement: function(form) {=0A= form =3D $(form);=0A= form.findFirstElement().activate();=0A= return form;=0A= },=0A= =0A= request: function(form, options) {=0A= form =3D $(form), options =3D Object.clone(options || { });=0A= =0A= var params =3D options.parameters, action =3D = form.readAttribute('action') || '';=0A= if (action.blank()) action =3D window.location.href;=0A= options.parameters =3D form.serialize(true);=0A= =0A= if (params) {=0A= if (Object.isString(params)) params =3D params.toQueryParams();=0A= Object.extend(options.parameters, params);=0A= }=0A= =0A= if (form.hasAttribute('method') && !options.method)=0A= options.method =3D form.method;=0A= =0A= return new Ajax.Request(action, options);=0A= }=0A= };=0A= =0A= /*-----------------------------------------------------------------------= ---*/=0A= =0A= Form.Element =3D {=0A= focus: function(element) {=0A= $(element).focus();=0A= return element;=0A= },=0A= =0A= select: function(element) {=0A= $(element).select();=0A= return element;=0A= }=0A= };=0A= =0A= Form.Element.Methods =3D {=0A= serialize: function(element) {=0A= element =3D $(element);=0A= if (!element.disabled && element.name) {=0A= var value =3D element.getValue();=0A= if (value !=3D undefined) {=0A= var pair =3D { };=0A= pair[element.name] =3D value;=0A= return Object.toQueryString(pair);=0A= }=0A= }=0A= return '';=0A= },=0A= =0A= getValue: function(element) {=0A= element =3D $(element);=0A= var method =3D element.tagName.toLowerCase();=0A= return Form.Element.Serializers[method](element);=0A= },=0A= =0A= setValue: function(element, value) {=0A= element =3D $(element);=0A= var method =3D element.tagName.toLowerCase();=0A= Form.Element.Serializers[method](element, value);=0A= return element;=0A= },=0A= =0A= clear: function(element) {=0A= $(element).value =3D '';=0A= return element;=0A= },=0A= =0A= present: function(element) {=0A= return $(element).value !=3D '';=0A= },=0A= =0A= activate: function(element) {=0A= element =3D $(element);=0A= try {=0A= element.focus();=0A= if (element.select && (element.tagName.toLowerCase() !=3D 'input' = ||=0A= !['button', 'reset', 'submit'].include(element.type)))=0A= element.select();=0A= } catch (e) { }=0A= return element;=0A= },=0A= =0A= disable: function(element) {=0A= element =3D $(element);=0A= element.blur();=0A= element.disabled =3D true;=0A= return element;=0A= },=0A= =0A= enable: function(element) {=0A= element =3D $(element);=0A= element.disabled =3D false;=0A= return element;=0A= }=0A= };=0A= =0A= /*-----------------------------------------------------------------------= ---*/=0A= =0A= var Field =3D Form.Element;=0A= var $F =3D Form.Element.Methods.getValue;=0A= =0A= /*-----------------------------------------------------------------------= ---*/=0A= =0A= Form.Element.Serializers =3D {=0A= input: function(element, value) {=0A= switch (element.type.toLowerCase()) {=0A= case 'checkbox':=0A= case 'radio':=0A= return Form.Element.Serializers.inputSelector(element, value);=0A= default:=0A= return Form.Element.Serializers.textarea(element, value);=0A= }=0A= },=0A= =0A= inputSelector: function(element, value) {=0A= if (value =3D=3D=3D undefined) return element.checked ? = element.value : null;=0A= else element.checked =3D !!value;=0A= },=0A= =0A= textarea: function(element, value) {=0A= if (value =3D=3D=3D undefined) return element.value;=0A= else element.value =3D value;=0A= },=0A= =0A= select: function(element, index) {=0A= if (index =3D=3D=3D undefined)=0A= return this[element.type =3D=3D 'select-one' ?=0A= 'selectOne' : 'selectMany'](element);=0A= else {=0A= var opt, value, single =3D !Object.isArray(index);=0A= for (var i =3D 0, length =3D element.length; i < length; i++) {=0A= opt =3D element.options[i];=0A= value =3D this.optionValue(opt);=0A= if (single) {=0A= if (value =3D=3D index) {=0A= opt.selected =3D true;=0A= return;=0A= }=0A= }=0A= else opt.selected =3D index.include(value);=0A= }=0A= }=0A= },=0A= =0A= selectOne: function(element) {=0A= var index =3D element.selectedIndex;=0A= return index >=3D 0 ? this.optionValue(element.options[index]) : = null;=0A= },=0A= =0A= selectMany: function(element) {=0A= var values, length =3D element.length;=0A= if (!length) return null;=0A= =0A= for (var i =3D 0, values =3D []; i < length; i++) {=0A= var opt =3D element.options[i];=0A= if (opt.selected) values.push(this.optionValue(opt));=0A= }=0A= return values;=0A= },=0A= =0A= optionValue: function(opt) {=0A= // extend element because hasAttribute may not be native=0A= return Element.extend(opt).hasAttribute('value') ? opt.value : = opt.text;=0A= }=0A= };=0A= =0A= /*-----------------------------------------------------------------------= ---*/=0A= =0A= Abstract.TimedObserver =3D Class.create(PeriodicalExecuter, {=0A= initialize: function($super, element, frequency, callback) {=0A= $super(callback, frequency);=0A= this.element =3D $(element);=0A= this.lastValue =3D this.getValue();=0A= },=0A= =0A= execute: function() {=0A= var value =3D this.getValue();=0A= if (Object.isString(this.lastValue) && Object.isString(value) ?=0A= this.lastValue !=3D value : String(this.lastValue) !=3D = String(value)) {=0A= this.callback(this.element, value);=0A= this.lastValue =3D value;=0A= }=0A= }=0A= });=0A= =0A= Form.Element.Observer =3D Class.create(Abstract.TimedObserver, {=0A= getValue: function() {=0A= return Form.Element.getValue(this.element);=0A= }=0A= });=0A= =0A= Form.Observer =3D Class.create(Abstract.TimedObserver, {=0A= getValue: function() {=0A= return Form.serialize(this.element);=0A= }=0A= });=0A= =0A= /*-----------------------------------------------------------------------= ---*/=0A= =0A= Abstract.EventObserver =3D Class.create({=0A= initialize: function(element, callback) {=0A= this.element =3D $(element);=0A= this.callback =3D callback;=0A= =0A= this.lastValue =3D this.getValue();=0A= if (this.element.tagName.toLowerCase() =3D=3D 'form')=0A= this.registerFormCallbacks();=0A= else=0A= this.registerCallback(this.element);=0A= },=0A= =0A= onElementEvent: function() {=0A= var value =3D this.getValue();=0A= if (this.lastValue !=3D value) {=0A= this.callback(this.element, value);=0A= this.lastValue =3D value;=0A= }=0A= },=0A= =0A= registerFormCallbacks: function() {=0A= Form.getElements(this.element).each(this.registerCallback, this);=0A= },=0A= =0A= registerCallback: function(element) {=0A= if (element.type) {=0A= switch (element.type.toLowerCase()) {=0A= case 'checkbox':=0A= case 'radio':=0A= Event.observe(element, 'click', = this.onElementEvent.bind(this));=0A= break;=0A= default:=0A= Event.observe(element, 'change', = this.onElementEvent.bind(this));=0A= break;=0A= }=0A= }=0A= }=0A= });=0A= =0A= Form.Element.EventObserver =3D Class.create(Abstract.EventObserver, {=0A= getValue: function() {=0A= return Form.Element.getValue(this.element);=0A= }=0A= });=0A= =0A= Form.EventObserver =3D Class.create(Abstract.EventObserver, {=0A= getValue: function() {=0A= return Form.serialize(this.element);=0A= }=0A= });=0A= if (!window.Event) var Event =3D { };=0A= =0A= Object.extend(Event, {=0A= KEY_BACKSPACE: 8,=0A= KEY_TAB: 9,=0A= KEY_RETURN: 13,=0A= KEY_ESC: 27,=0A= KEY_LEFT: 37,=0A= KEY_UP: 38,=0A= KEY_RIGHT: 39,=0A= KEY_DOWN: 40,=0A= KEY_DELETE: 46,=0A= KEY_HOME: 36,=0A= KEY_END: 35,=0A= KEY_PAGEUP: 33,=0A= KEY_PAGEDOWN: 34,=0A= KEY_INSERT: 45,=0A= =0A= cache: { },=0A= =0A= relatedTarget: function(event) {=0A= var element;=0A= switch(event.type) {=0A= case 'mouseover': element =3D event.fromElement; break;=0A= case 'mouseout': element =3D event.toElement; break;=0A= default: return null;=0A= }=0A= return Element.extend(element);=0A= }=0A= });=0A= =0A= Event.Methods =3D (function() {=0A= var isButton;=0A= =0A= if (Prototype.Browser.IE) {=0A= var buttonMap =3D { 0: 1, 1: 4, 2: 2 };=0A= isButton =3D function(event, code) {=0A= return event.button =3D=3D buttonMap[code];=0A= };=0A= =0A= } else if (Prototype.Browser.WebKit) {=0A= isButton =3D function(event, code) {=0A= switch (code) {=0A= case 0: return event.which =3D=3D 1 && !event.metaKey;=0A= case 1: return event.which =3D=3D 1 && event.metaKey;=0A= default: return false;=0A= }=0A= };=0A= =0A= } else {=0A= isButton =3D function(event, code) {=0A= return event.which ? (event.which =3D=3D=3D code + 1) : = (event.button =3D=3D=3D code);=0A= };=0A= }=0A= =0A= return {=0A= isLeftClick: function(event) { return isButton(event, 0) },=0A= isMiddleClick: function(event) { return isButton(event, 1) },=0A= isRightClick: function(event) { return isButton(event, 2) },=0A= =0A= element: function(event) {=0A= var node =3D Event.extend(event).target;=0A= return Element.extend(node.nodeType =3D=3D Node.TEXT_NODE ? = node.parentNode : node);=0A= },=0A= =0A= findElement: function(event, expression) {=0A= var element =3D Event.element(event);=0A= return element.match(expression) ? element : = element.up(expression);=0A= },=0A= =0A= pointer: function(event) {=0A= return {=0A= x: event.pageX || (event.clientX +=0A= (document.documentElement.scrollLeft || = document.body.scrollLeft)),=0A= y: event.pageY || (event.clientY +=0A= (document.documentElement.scrollTop || = document.body.scrollTop))=0A= };=0A= },=0A= =0A= pointerX: function(event) { return Event.pointer(event).x },=0A= pointerY: function(event) { return Event.pointer(event).y },=0A= =0A= stop: function(event) {=0A= Event.extend(event);=0A= event.preventDefault();=0A= event.stopPropagation();=0A= event.stopped =3D true;=0A= }=0A= };=0A= })();=0A= =0A= Event.extend =3D (function() {=0A= var methods =3D Object.keys(Event.Methods).inject({ }, function(m, = name) {=0A= m[name] =3D Event.Methods[name].methodize();=0A= return m;=0A= });=0A= =0A= if (Prototype.Browser.IE) {=0A= Object.extend(methods, {=0A= stopPropagation: function() { this.cancelBubble =3D true },=0A= preventDefault: function() { this.returnValue =3D false },=0A= inspect: function() { return "[object Event]" }=0A= });=0A= =0A= return function(event) {=0A= if (!event) return false;=0A= if (event._extendedByPrototype) return event;=0A= =0A= event._extendedByPrototype =3D Prototype.emptyFunction;=0A= var pointer =3D Event.pointer(event);=0A= Object.extend(event, {=0A= target: event.srcElement,=0A= relatedTarget: Event.relatedTarget(event),=0A= pageX: pointer.x,=0A= pageY: pointer.y=0A= });=0A= return Object.extend(event, methods);=0A= };=0A= =0A= } else {=0A= Event.prototype =3D Event.prototype || = document.createEvent("HTMLEvents").__proto__;=0A= Object.extend(Event.prototype, methods);=0A= return Prototype.K;=0A= }=0A= })();=0A= =0A= Object.extend(Event, (function() {=0A= var cache =3D Event.cache;=0A= =0A= function getEventID(element) {=0A= if (element._eventID) return element._eventID;=0A= arguments.callee.id =3D arguments.callee.id || 1;=0A= return element._eventID =3D ++arguments.callee.id;=0A= }=0A= =0A= function getDOMEventName(eventName) {=0A= if (eventName && eventName.include(':')) return "dataavailable";=0A= return eventName;=0A= }=0A= =0A= function getCacheForID(id) {=0A= return cache[id] =3D cache[id] || { };=0A= }=0A= =0A= function getWrappersForEventName(id, eventName) {=0A= var c =3D getCacheForID(id);=0A= return c[eventName] =3D c[eventName] || [];=0A= }=0A= =0A= function createWrapper(element, eventName, handler) {=0A= var id =3D getEventID(element);=0A= var c =3D getWrappersForEventName(id, eventName);=0A= if (c.pluck("handler").include(handler)) return false;=0A= =0A= var wrapper =3D function(event) {=0A= if (!Event || !Event.extend ||=0A= (event.eventName && event.eventName !=3D eventName))=0A= return false;=0A= =0A= Event.extend(event);=0A= handler.call(element, event)=0A= };=0A= =0A= wrapper.handler =3D handler;=0A= c.push(wrapper);=0A= return wrapper;=0A= }=0A= =0A= function findWrapper(id, eventName, handler) {=0A= var c =3D getWrappersForEventName(id, eventName);=0A= return c.find(function(wrapper) { return wrapper.handler =3D=3D = handler });=0A= }=0A= =0A= function destroyWrapper(id, eventName, handler) {=0A= var c =3D getCacheForID(id);=0A= if (!c[eventName]) return false;=0A= c[eventName] =3D c[eventName].without(findWrapper(id, eventName, = handler));=0A= }=0A= =0A= function destroyCache() {=0A= for (var id in cache)=0A= for (var eventName in cache[id])=0A= cache[id][eventName] =3D null;=0A= }=0A= =0A= if (window.attachEvent) {=0A= window.attachEvent("onunload", destroyCache);=0A= }=0A= =0A= return {=0A= observe: function(element, eventName, handler) {=0A= element =3D $(element);=0A= var name =3D getDOMEventName(eventName);=0A= =0A= var wrapper =3D createWrapper(element, eventName, handler);=0A= if (!wrapper) return element;=0A= =0A= if (element.addEventListener) {=0A= element.addEventListener(name, wrapper, false);=0A= } else {=0A= element.attachEvent("on" + name, wrapper);=0A= }=0A= =0A= return element;=0A= },=0A= =0A= stopObserving: function(element, eventName, handler) {=0A= element =3D $(element);=0A= var id =3D getEventID(element), name =3D = getDOMEventName(eventName);=0A= =0A= if (!handler && eventName) {=0A= getWrappersForEventName(id, eventName).each(function(wrapper) {=0A= element.stopObserving(eventName, wrapper.handler);=0A= });=0A= return element;=0A= =0A= } else if (!eventName) {=0A= Object.keys(getCacheForID(id)).each(function(eventName) {=0A= element.stopObserving(eventName);=0A= });=0A= return element;=0A= }=0A= =0A= var wrapper =3D findWrapper(id, eventName, handler);=0A= if (!wrapper) return element;=0A= =0A= if (element.removeEventListener) {=0A= element.removeEventListener(name, wrapper, false);=0A= } else {=0A= element.detachEvent("on" + name, wrapper);=0A= }=0A= =0A= destroyWrapper(id, eventName, handler);=0A= =0A= return element;=0A= },=0A= =0A= fire: function(element, eventName, memo) {=0A= element =3D $(element);=0A= if (element =3D=3D document && document.createEvent && = !element.dispatchEvent)=0A= element =3D document.documentElement;=0A= =0A= if (document.createEvent) {=0A= var event =3D document.createEvent("HTMLEvents");=0A= event.initEvent("dataavailable", true, true);=0A= } else {=0A= var event =3D document.createEventObject();=0A= event.eventType =3D "ondataavailable";=0A= }=0A= =0A= event.eventName =3D eventName;=0A= event.memo =3D memo || { };=0A= =0A= if (document.createEvent) {=0A= element.dispatchEvent(event);=0A= } else {=0A= element.fireEvent(event.eventType, event);=0A= }=0A= =0A= return event;=0A= }=0A= };=0A= })());=0A= =0A= Object.extend(Event, Event.Methods);=0A= =0A= Element.addMethods({=0A= fire: Event.fire,=0A= observe: Event.observe,=0A= stopObserving: Event.stopObserving=0A= });=0A= =0A= Object.extend(document, {=0A= fire: Element.Methods.fire.methodize(),=0A= observe: Element.Methods.observe.methodize(),=0A= stopObserving: Element.Methods.stopObserving.methodize()=0A= });=0A= =0A= (function() {=0A= /* Support for the DOMContentLoaded event is based on work by Dan Webb,=0A= Matthias Miller, Dean Edwards and John Resig. */=0A= =0A= var timer, fired =3D false;=0A= =0A= function fireContentLoadedEvent() {=0A= if (fired) return;=0A= if (timer) window.clearInterval(timer);=0A= document.fire("dom:loaded");=0A= fired =3D true;=0A= }=0A= =0A= if (document.addEventListener) {=0A= if (Prototype.Browser.WebKit) {=0A= timer =3D window.setInterval(function() {=0A= if (/loaded|complete/.test(document.readyState))=0A= fireContentLoadedEvent();=0A= }, 0);=0A= =0A= Event.observe(window, "load", fireContentLoadedEvent);=0A= =0A= } else {=0A= document.addEventListener("DOMContentLoaded",=0A= fireContentLoadedEvent, false);=0A= }=0A= =0A= } else {=0A= document.write("