晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳精品课件

NSCLCProgress in the treatment 晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂 的最佳治疗易瑞沙与特罗凯的比较 蔡蔡 俊俊 明明 台北榮民總醫院台北榮民總醫院 胸腔部胸腔部 胸腔腫瘤科胸腔腫瘤科 陽明大學陽明大學 醫學院醫學院 內科學系內科學系 三十年来晚期非小细胞肺癌的治疗成果 I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 for patients independent of histology 2009 2008 2007 1998 1995 1990s 1970s 1950s MST (months) BSC Cis monotherapy Pt/VP-16 Pt/Doc Pt/Pac Pt/Gem Pt/NVB 10.9 (GC) v. 12.6, HR=0.84 JMDB Adeno.Cis/Pem Non-squamous Pac/Cb/Avastin 10.3 v. 12.3, HR=0.79 20.4 v. 17.6 NVB/Cis/Erbitux 10.1 v. 11.3, HR=0.871 13.1 v. 13.6, HR=0.93 17.4 v. 28.2, HR=0.46 Gem/Cis/Avastin EGFR-TKIs 12.5 v. 18.1, HR=0.66 All Adeno. 13.6 v. 27.2, HR=0.48 Mutations 15.6 v. 29.2, HR=0.48ex19 ChemotherapyChemotherapyTargeted TherapyTargeted Therapy CM Tsai 2009 Tumour cellTumour cell proliferationproliferation PI3K MAPK Tumour cellTumour cell survivalsurvival Akt mTOR STAT 3/5 Grb-2 Ras Raf MEK ATP Anti-EGFR Abs Cetuximab, Panitumumab, Matuzumab, h-R3, MDX-447 Anti-HER1,HER2,HER4 TKIs Gefitinib, Erlotinib, BIBW-2992, PKI- 166, GW-572016, CI-1033, AEE788 RAS farnesyltransferase inhibitors MMS214662, R115777, SCH66336 RAF inhibitors Sorafenib, L-779450 MEK inhibitors CI-1040, U-0126 mTOR inhibitors Temsirolimus, RAD001 I I I I I I I I I I I I ATP SOS Small molecule Small molecule tyrosine kinase inhibitorstyrosine kinase inhibitors 表皮生长因子受体讯息传递的生物标记与抑制剂 肺腺癌的表皮生长因子受体突变 Response Rate vs. Clinical Background Clinical Background vs. EGFR Mutations EGFR mutation (%)RR (%) Asian Non-Asian Female Male Never Ever Adeno Non-Adeno Asian Non-Asian Female Male Never Ever Adeno Non-Adeno Mitsudomi, IJCO, 2006 T854AE884KE884K L747S D761Y 敏感性突变 Sharma, et al. Nat Rev Cancer 2007 生长因子受体易瑞沙与特罗凯的敏感性突变 抗药性突变 100 55 125 288 283 104 102 100 55 125 288 283 104 102 TAX317 TAX320 JMEI IDEAL1 IDEAL2 TAX317 TAX320 JMEI IDEAL1 IDEAL2 2929 Gefitinib 7.67.6 6.56.5 66.866.858.658.6 11.811.818.418.4 Gefitinib 3535 100 55 125 288 283 104 102 100 55 125 288 283 104 102 TAX317 TAX320 JMEI IDEAL1 IDEAL2 TAX317 TAX320 JMEI IDEAL1 IDEAL2 2222 3131 BSC Erlotinib 4.74.7 6.76.7 2828 5353 8.98.9 100 55 125 288 283 104 102 563 1126 243 488 100 55 125 288 283 104 102 563 1126 243 488 TAX317 TAX320 JMEI IDEAL1 IDEAL2 ISEL BR21TAX317 TAX320 JMEI IDEAL1 IDEAL2 ISEL BR21 2121 2727 BSC Gefitinib 5.15.1 5.65.6 3232 4848 8 8 HR= 0.89HR= 0.89 P= 0.087P= 0.087 0.700.70 85% inhibition at 2 85% inhibition at 2 MM Identification 3 compoundsIdentification 3 compounds CL-387,785; EKB-569; CI-1033CL-387,785; EKB-569; CI-1033 Determine IC50Determine IC50Measure EGFRMeasure EGFR Autophos inhibitionAutophos inhibition Ambit BiosciencesAmbit Biosciences Compound ICCompound IC5050 ( ( M)M) CI-1033CI-10330.0230.023 EKB-569 EKB-569 0.0330.033 CL-387,785CL-387,7850.0510.051 SU-11464 SU-114640.4500.450 ZD6474 ZD64741.9001.900 GW572016 GW5720163.5003.500 Gefitinib Gefitinib6.6006.600 PKI-166 PKI-1667.7007.700 Erlotinib Erlotinib10.00010.000 Inhibition of H1975 cell proliferationInhibition of H1975 cell proliferation 克服T790M抗药性药物之研究 Incidence of AEs (%)*Incidence of AEs (%)* Erlotinib (n=485)Erlotinib (n=485)GefitinibGefitinib (n=1,126)(n=1,126) AllAllGrade 3+Grade 3+AllAllGrade 3+Grade 3+ RashRash7676 9 9 3737 2 2 DiarrheaDiarrhea5555 6 6 2727 3 3 NauseaNausea4040 3 3 1717 1 1 AnorexiaAnorexia6969 9 9 1717 2 2 VomitingVomiting2525 3 3 1414 1 1 Dry skinDry skin1212 0 0 1111 0 0 易瑞沙与特罗凯：副作用表列 易瑞沙与特罗凯做为晚期非小细胞肺癌 后线治疗的比较 逆溯性配对研究 Sungkyunkwan University, School of Medicine Samsung Medical Center Myung-Ju Ahn, M.D. Characteristics Gefitinib (N=174) Erlotinib (N=174) P-value Age Median (Range)58.0 (25.0-87.0)59.0 (20.0-82.0) 60 years100100 NA 60 years7474 Sex Male111111 NA Female6363 ECOG 0-1116116 NA 25858 Histology Adenocarcinoma125125 NA Non-adenoca.4949 No of prior chemo 2145145 NA 2 2/18 2nd stage: additional 25 pts 方方 法法 R A N D O M I Z A T IO N Gefitinib 250mg/d Q4wKs Erlotinib 150mg/d Q4wks R E E V A L U A T IO N R E E V A L U A T IO N Until Disease progression or Intolerable toxicities 4 weeks 8 weeks At least 2 of 3 l Adenoca. l Female l Never smoker or EGFR mutant 病患基本资料 Characteristics Characteristics All All (n=96, %)(n=96, %) GefitinibGefitinib (n=48, %)(n=48, %) ErlotinibErlotinib (n=48, %)(n=48, %) P valueP value Age (yrs)Age (yrs) MedianMedian Range Range 5959 32-8332-83 6060 37-8337-83 5656 32-8132-81 0.1610.161 Sex Sex MaleMale Female Female 14 (14.6)14 (14.6) 82 82 (85.4)(85.4) 7 (14.6)7 (14.6) 41 (85.4)41 (85.4) 7 (14.6)7 (14.6) 41 (85.4)41 (85.4) 1.0001.000 ECOG PSECOG PS 1 1 2 2 82 (85.4)82 (85.4) 14 (14.6)14 (14.6) 41 (85.4)41 (85.4) 7 (14.6)7 (14.6) 41 (85.4)41 (85.4) 7 (14.6)7 (14.6) 1.0001.000 Stage Stage IIIBIIIB IVIV RecurredRecurred 12 (12.5)12 (12.5) 69 (71.9)69 (71.9) 13 (13.5)13 (13.5) 7 (14.6)7 (14.6) 35 (72.9)35 (72.9) 6 (12.5)6 (12.5) 5 (10.4)5 (10.4) 34 (70.8)34 (70.8) 7 (14.6)7 (14.6) 0.4890.489 HistologyHistology AdenocarcinomaAdenocarcinoma SquamousSquamous OthersOthers 87 87 (90.6)(90.6) 6 (6.3)6 (6.3) 3 (3.1)3 (3.1) 44 (91.7)44 (91.7) 3 (6.3)3 (6.3) 1 (2.1)1 (2.1) 43 (89.6)43 (89.6) 3 (6.3)3 (6.3) 2 (4.1)2 (4.1) 0.7980.798 Prior Prior treatmenttreatment Neoadjuvant CCRTNeoadjuvant CCRT Adjuvant CCRTAdjuvant CCRT Adjuvant ChemoAdjuvant Chemo Definitive CCRTDefinitive CCRT Platinum ChemoPlatinum Chemo 2 (2.1)2 (2.1) 3 (3.1)3 (3.1) 5 (5.2)5 (5.2) 3 (3.1)3 (3.1) 93 (96.9)93 (96.9) 1 (2.1)1 (2.1) 2 (4.2)2 (4.2) 2 (4.2)2 (4.2) 2 (4.2)2 (4.2) 45 (93.8)45 (93.8) 1 (2.1)1 (2.1) 1 (2.1)1 (2.1) 3 (6.3)3 (6.3) 1 (2.1)1 (2.1) 48 (100)48 (100) 0.0780.078 SmokingSmoking Ever-smokerEver-smoker Never-smokerNever-smoker 6 (6.2)6 (6.2) 90 90 (93.7)(93.7) 4 (8.3)4 (8.3) 44 (91.7)44 (91.7) 2 (4.2)2 (4.2) 46 (95.8)46 (95.8) 0.5120.512 EGFR EGFR mutationmutation EGFR mutationEGFR mutation Wild typeWild type Not testedNot tested 17 (17.7)17 (17.7) 23 (24.0)23 (24.0) 56 (58.3)56 (58.3) 9 (18.8)9 (18.8) 8 (16.7)8 (16.7) 31 (64.6)31 (64.6) 8 (16.7)8 (16.7) 15 (31.3)15 (31.3) 25 (52.1)25 (52.1) 0.2430.243 Numbers of treatment cycles : median 5 (range, 0.5-20), total 605 cyclesNumbers of treatment cycles : median 5 (range, 0.5-20), total 605 cycles Gefitinib group: median 6 (range, 0.5-19), total 331 cyclesGefitinib group: median 6 (range, 0.5-19), total 331 cycles Erlotinib group: median 4 (range, 0.5-20), total 274 cyclesErlotinib group: median 4 (range, 0.5-20), total 274 cycles Gefitinib Gefitinib Erlotinib Erlotinib P P value value N N (n=48)(n=48) % N N (n=48)(n=48) % CRCR 1 1 2.12.1 1 1 2.12.1 0.9420.942 PRPR222245.845.8181837.537.5 SDSD121225.025.0131327.127.1 PDPD121225.025.0151531.331.3 NENE 1 1 2.12.1 1 1 2.12.1 ORRORR232347.9 (33.8-62.0)47.9 (33.8-62.0)191939.6 (25.8-53.4)39.6 (25.8-53.4)0.4110.411 DCRDCR353572.9 (60.3-85.4)72.9 (60.3-85.4)323266.7 (53.4-80.0)66.7 (53.4-80.0)0.5050.505 肿瘤反应 整体与无恶化存活曲线 Median follow-up duration: 11.5 months (range, 6.7-20.8) Median (95% CI) 20.4 months (8.8-32.0) 4.8 months (2.7-6.9) Gefitinib Erlotinib PFS by Treatment P=0.167 Median PFS (95% CI) 4.9 months (1.5-8.3) 3.1 months (0.0-6.4) OS and PFS OS PFS 毒性副作用 GefitinibErlotinib Toxicity gradeToxicity grade 123Total123Total P value Skin rash 25 (52.1)4 (8.3)1 (2.1)30 (62.5)14 (29.2)16 (33.3)5 (10.4) 35 (72.9)0.003 Dry skin 8 (16.7)0 (0)- 8 (16.7)9 (18.8)1 (2.1)-10 (20.9)0.733 Paronychia 4 (8.3)1 (2.1)-5 (10.4)4 (8.3)0 (0)-4 (8.3)0.767 Diarrhea 8 (16.7)8 (16.7)-16 (33.4)14 (29.2)3 (6.3)-17 (35.5)0.238 Mucositis 1 (2.1)2 (4.2)-3 (6.3)4 (8.3)1 (2.1)-5 (10.4)0.300 Fatigue 0 (0)0 (0)- 0 (0)5 (10.4)3 (3.1)-8 (16.7)0.027 Anorexia 7 (14.6)0 (0)-7 (14.6)4 (8.3)1 (2.1)-5 (10.4)0.587 Alopecia 3 (6.3)- 3 (6.3)1 (2.1)-1 (2.1)0.463 Neuropathy 2 (4.2)2 (4.2)-4 (8.4)3 (6.3)0 (0)-3 (6.3)0.414 Infection -1 (2.1)1 (2.1)-1 (2.1)1 (2.1)1.000 ILD - Except 3 mortalities from pneumonia. (2 of gefitinib and 1 of erlotinib) 表皮生长因子受体突变患者的 临床后果 非小细胞肺癌患者接受表皮生长因子受体非小细胞肺癌患者接受表皮生长因子受体 酪氨酸抑制剂或化疗的集体分析酪氨酸抑制剂或化疗的集体分析 L Paz-Ares, et al. ESMO/ECCO Berlin 2009 J Cell Mol Med 2010 14:51-69 论文搜集策略摘要论文搜集策略摘要 Reports identified from broad literature search (n=564) Studies retained for full paper review (n=175) Studies identified from ASCO 20089 search (+n=42) Excluded based on abstract or title: no clinical data related to question (- n=431) Excluded (n=121) PFS/TTP/n not reported for pts with mutations (n=96) EGFR-TKIs given sequentially or as maintenance or adjuvant therapy (n=10) Data duplicated in another publication (n=15) Studies included (n=54) 资料搜集策略摘要 ErlotinibGefitinibChemotherapy Pts treated in any line; n3651,069375 Pts treated in first-line setting 57%57%95% Total number of patients = 1,809 (65% treated in first-line setting) 个别研究之疾病无恶化期 90% accuracy intervals (any line of therapy) Erlotinib Gefitinib Chemotherapy Pooled median PFS (95% accuracy interval) 13.2 (12.014.7) 9.8 (9.210.4) 5.9 (5.36.5) Permutation test for estimated pooled median PFS (1,000 iterations) EGFR TKI vs chemotherapy p=0.000 (two-sided) Erlotinib N = 365 (2/12) Gefitinib N = 1069 (19/39) Chemotherapy N = 375 Pooled studies 表皮生长长因子受体突变变阳性 各种治疗疗疗疗 效 SATURN 研究設計 Stratification factors: lEGFR IHC (positive vs negative vs indeterminate) lStage (IIIB vs IV) lECOG PS (0 vs 1) lCT regimen (cis/gem vs carbo/doc vs others) lSmoking history (current vs former vs never) lRegion 1:1 Chemonave advanced NSCLC n=1,949 Non-PD n=889 4 cycles of 1st-line platinum- based doublet* PlaceboPD Erlotinib 150mg/day PD Mandatory tumour sampling *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel EGFR = epidermal growth factor receptor; IHC = immunohistochemistry Co-primary endpoints: lPFS in all patients lPFS in patients with EGFR IHC+ tumours Secondary endpoints: lOverall survival (OS) in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL) 晚期非小细胞肺癌含铂两药方案后以易瑞沙治疗或 持续化疗之随机第三相研究: WJTOG试验结果 LBA#8012 全 部 肺腺癌 WJTOG 0203 - OS 非鳞状细胞癌 SATURN - OS 全 部 WJTOG0203: 整体存活依临床特质之亚群分析 0.40.60.81.01.2 Favours erlotinib Favours placebo HR Male Female Caucasian Asian Adenocarcinoma Squamous-cell Never smoker Former smoker Current smoker HR (95% CI)n 0.88 (0.741.05)659 0.64 (0.460.91)230 0.86 (0.731.01)746 0.66 (0.421.05)131 0.77 (0.610.97)403 0.86 (0.681.10)360 0.69 (0.451.05)152 0.75 (0.561.00)244 0.88 (0.721.08)493 All0.81 (0.700.95)889 SATURN: 整体存活依临床特质之亚群分析 SATURN: 疾病无恶化期 (野生型 vs.鳞状细胞癌鳞状细胞癌 ) Log-rank p=0.0148 HR=0.76 (0.600.95) 鳞状细胞癌鳞状细胞癌 1.0 0.8 0.6 0.4 0.2 0 Time (weeks) 0 8 16 24 32 40 48 56 64 72 80 88 Erlotinib (n=166) Placebo (n=193) PFS probability Log-rank p=0.0185 HR=0.78 (0.630.96) 1.0 0.8 0.6 0.4 0.2 0 Time (weeks) Erlotinib (n=199) Placebo (n=189) 0 8 16 24 32 40 48 56 64 72 80 88 96 EGFR EGFR 野生型野生型 台湾晚期非小台湾晚期非小细细胞肺癌易瑞沙与特胞肺癌易瑞沙与特罗凯罗凯 的比的比较较 多中心逆溯型研究多中心逆溯型研究 胸腔醫學會胸腔醫學會 2009 2009 北榮北榮 范紋健范紋健 Total:1122Female45% Never/light smoker53% Adenocarcinoma77% Stage IV79% Chemo-naive41% GefitinibErlotinib*P N715407 ORR34.4%35.6%0.68 DCR58.9%65.6%0.02 PFS3.6 m4.6 m * Erlotinib group: more male, smoker and non-adeno. 一非小细胞肺癌具有表皮生长 因子受体突变*并合并脑膜转移 病例以高剂量易瑞沙治疗的 反应与抗药性 Pasi A. Janne and Bruce E. Johnson JCO 200612/2004 09/2004 *Exon 19 deletion, IC50: 10-50 nM. 特罗凯对初期对易瑞沙有疗效之肺腺癌并有脑 部与脑膜转移患者的疗效 Katayama, et al. JTO 2009 Response to erlotinib based on RECIST (N=24) 以特罗凯治疗易瑞沙治疗后失败的非小细胞 肺癌的第二相研究 Shih et al, WCLC 2007 07/13/2006 10/09/2006 Intracranial lesions: minimal response 特罗凯用于易瑞沙治疗恶化之后 女性女性/1953 /1953 肺腺癌合并脑部转移肺腺癌合并脑部转移 20032003 01 0201 02 WBRTWBRT 20032003 03 0603 06 Gem/CisGem/Cis X 6X 6 20042004 02 0602 06 DocDoc X 6X 6 2004 - 052004 - 05 10 0210 02 NVB/IfoNVB/Ifo X 6X 6 2005 20082005 2008 05 04 05 04 20072007 04 0504 05 WBRTWBRT 2008 02/12-25 Erlotinib 2008/02/05 2008/02/26 2008/02/05 2008/02/262008/04/222008/04/22 GefitinibGefitinib 易瑞沙易瑞沙 (250 mg daily)(250 mg daily) 特罗凯特罗凯 (150 mg daily)(150 mg daily) 稳稳稳稳定血清定血清浓浓浓浓度度 ( ( MM ) ) 0.40.41.12 3.41.12 3.4 非小非小细细细细胞肺癌胞肺癌细细细细胞株胞株 ICIC50 50 ( ( M)M) 野生型野生型 活化性突活化性突变变变变 1 1 1 1 0.050.05 肿肿肿肿瘤有活化性瘤有活化性EGFREGFR突突 变变变变病人病人 较优较优较优较优 , , 毒性毒性较较较较少少 有效有效, , 毒性毒性较较较较大大 肿肿肿肿瘤是瘤是EGFREGFR野生型病野生型病 人人 效果不好效果不好 略微有效略微有效, , 优于易优于易 瑞沙瑞沙, , 化疗较好化疗较好 临床应用临床应用: : Tsai CM, 2010Tsai CM, 2010 易瑞沙易瑞沙 (250 mg daily)(250 mg daily) 特罗凯特罗凯 (150 mg daily)(150 mg daily) IPASSIPASS组群组群* *有效有效 有效有效, , 毒性毒性较较较较大大 非非IPASSIPASS组群组群可能效果不好可能效果不好 优于易瑞沙优于易瑞沙, , 化疗较好化疗较好 肿肿肿肿瘤有活化性瘤有活化性EGFREGFR突突 变变变变并脑部转移并脑部转移病人病人 有效有效 较有效较有效, ,毒性较大毒性较大 可延后到易瑞沙治可延后到易瑞沙治 疗失败疗失败(?)(?) Tsai CM, 2010Tsai CM, 2010 * *不吸烟与轻度吸烟已戒烟之肺腺癌不吸烟与轻度吸烟已戒烟之肺腺癌 临床应用临床应用: : Vv4Nm*EeXw5Oo)GfYy7Qp-Ih#z8Sr0Ji!BaTs1Lk%CbVu3Ml*EdWv5On(FeYx6Po-HgZy8Rq+Ii!A9Ss1Kj$BbUt2Ll&DcVv4Nm*FeXw5Po)GfZy7Qp-Ih#z8Sr0Ji$BaTs2Lk%CcVu3Ml*EdWv5On(FfYx6Pp-HgZz8Rq+Ii!A9Ss1Kj$CbUt2Ml&DcWv4Nm*FeXw5Po)GfZy7Qp+Ih#z9Sr0Ji$BaTs2Lk%CcVu3Mm*EdWw5On(FfYx6Pp-HgZz8Rq+Ji!A9Ts1Kj$CbUt2Ml&DcWv4Nm(FeXw6Po)GgZy7Qp+Ih#z9Sr0Jj$BaTt2Lk%DcVu3Mm*EdWw5On(GfYx6Qp- Hg#z8Rq+Ji!A9Ts1Kj%CbUt3Ml&DdWv4Nm(FeXw6Po)GgZy7Qq+Ih#A9Sr0Jj$BaTt2Lk%DcVu3Nm*EdXw5On(GfYx6Qp-Hg#z8Rq0Ji!AaTs1Kj%CbUt3Ml&DdWv4Nn(Fe!A9Sr1Kj$BaUt2Lk&DcVu4Nm*EeXw5Oo)GfYx7Qp-Hh#z8Rr0Ji!BaTs1Lk%CbVu3Ml&EdWv4On(FeYx6Po-HgZy8Rq+Ih!A9Sr1Kj$BbUt2Ll&DcVv4Nm*EeXw5Oo)GfYy7Qp-Ih#z8Sr0Ji!BaTs1Lk%CbVu3Ml*EdWv5On(FeYx6Po-HgZy8Rq+Ii!A9Ss1Kj$BbUt2Ll&DcVv4Nm*FeXw5Po)GfYy7Qp-Ih#z8Sr0Ji$BaTs2Lk%CcVu3Ml*EdWv5On(FfYx6Pp- HgZz8Rq+Ii!A9Zy7Qq+Ih#A9Sr0Kj$BaUt2Lk%DcVu3Nm*EdXw5On)GfYx7Qp-Hg#z8Rq0Ji!AaTs1Kk%CbUu3Ml&DdWv4Nn(FeXx6Po)HgZy7Rq+Ih!A9Sr0Kj$BaUt2Lk&DcVu4Nm*EeXw5On)GfYx7Qp-Hh#z8Rr0Ji!BaTs1Kk%CbUu3Ml&EdWv4On(FeYx6Po)HgZy7Rq+Ih!A9Sr1Kj$BbUt2Lk&DcVu4Nm*EeXw5Oo)GfYy7Qp-Hh#z8Rr0Ji!BaTs1Lk%CbVu3Ml&EdWv4On(FeYx6Po-HgZy8Rq+Ii!A9Sr1Kj$BbUt2Ll&DcVv4Nm*FeXw5Oo)GfYy7Qp-Ih#z8Sr0Ji$BaTs1Lk%CbVu3Ml*EdWv5On(FfYx6Po- HgZy8Rq+Ii!A9Ss1Kj$CbUt2Ll&DcVv4Nm*FeXw5Po)GfZy7Qp-Ih#z8Sr0Ji$BaTs2Lk%CcVu3Mm*EdWv5On(FfYx6Pp-HgZz8Rq+Ji!A9Ss1Kj$CbXw6Po)GgZy7Qq+Ih#z9Sr0Jj$BaTt2Lk%DcVu3Nm*EdXw5On(GfYx6Qp-Hg#z8Rq0Ji!AaTs1Kj%CbUt3Ml&DdWv4Nn(FeXx6Po)GgZy7Qq+Ih#A9Sr0Kj$BaUt2Lk%DcVu3Nm*EdXw5On)GfYx7Qp-Hg#z8Rq0Ji!AaTs1Kk%CbUu3Ml&DdWv4Nn(FeXx6Po)HgZy7Rq+Ih#A9Sr0Kj$BaUt2Lk&DcVu4Nm*EeXw5On)GfYx7Qp- Hh#z8Rr0Ji!BaTs1Kk%CbUu3Ml&EdWv4On(FeYx6Po)HgZy7Rq+Ih!A9Sr1Kj$BbUt2Lk&DcVu4Nm*EeXw5Oo)GfYy7Qp-Hh#z8Rr0Ji!BaTs1Lk%CbVu3Ml&EdWv4On(FeYx6Po-HgZy8Rq+Ii!A9Sr1Kj$BbUt2Ll&DcVv4Nm*FeXw5Oo)GfYy7Qp-Ih#z8Sr0Ji$BaTs1Lk%CbVu3Ml*EdWv5On(FfYx6Po-HgZy8Rq+Ii!A9Ss1Kj$CbUt2Ll&DcVv4Nm*FeXw5Sr0Jj$BaTt2Lk%CcVu3Mm*EdWw5On(GfYx6Qp-HgZz8Rq+Ji!A9Ts1Kj%CbUt3Ml&DcWv4Nm(FeXw6Po)GgZy7Qq+Ih#z9Sr0Jj$BaTt2Lk%DcVu3Nm*EdXw5On(GfYx6Qp- Hg#z8Rq0Ji!AaTs1Kj%CbUt3Ml&DdWv4Nn(FeXx6Po)GgZy7Qq+Ih#A9Sr0Kj$BaUt2Lk%DcVu3Nm*EdXw5On)GfYx7Qp-Hg#z8Rq0Ji!AaTs1Kk%CbUu3Ml&DdWv4Nn(FeXx6Po)HgZy7Rq+Ih#A9Sr0Kj$BaUt2Lk&DcVu4Nm*EeXw5On)GfYx7Qp-Hh#z8Rr0Ji!BaTs1Kk%CbUu3Ml&EdWv4On(FeYx6Po)HgZy7Rq+Ih!A9Sr1Kj$BbUt2Lk&DcVu4Nm*EeXw5Oo)GfYy7Qp-Hh#z8Rr0Ji!BaTs1Lk%CbVu3Ml&EdWv4On(FeYx6Po-HgZy8Rq+Ih!A9Sr1Kj$BbUt2Ll&DcVv4Nm*FeXw5Oo)GfYy7Qp-Ih#z8Sr0Ji$BaTs1Lk%CbVu3Ml*EdWv5On(FfYx6Po- HgZy8Rq+Ii!A9Ss1Kj$CbUt2Ll&DcVv4Nm*FeXw5Po)GfZy7Qp-Ih#z8Sr0Ji$BaTs2Lk%CcVu3Ml*EdWv5On(FfYx6Pp-HgZz8Rq+Ji!A9Ss1Kj$CbUt2Ml&DcWv4Nm(FeXw5Po)GfZy7Qp+Ih#z9Sr0Jj$BaTs2Lk%CcVu3Mm*EdWw5On(GfYx6Pp-HgZz8Rq+Ji!A9Ts1Kj%CbUt2Ml&DcWv4Nm(FeXw6Po)Gj$BaUt2Lk%DcVu3Nm*EdXw5On)GfYx7Qp-Hg#z8Rq0Ji!AaTs1Kk%CbUu3Ml&DdWv4Nn(FeXx6Po)HgZy7Rq+Ih#A9Sr0Kj$BaUt2Lk&DcVu4Nm*EdXw5On)GfYx7Qp- Hh#z8Rr0Ji!BaTs1Kk%CbUu3Ml&EdWv4On(FeYx6Po)HgZy7Rq+Ih!A9Sr1Kj$BbUt2Lk&DcVu4Nm*EeXw5Oo)GfYy7Qp-Hh#z8Rr0Ji!BaTs1Lk%CbVu3Ml&EdWv4On(FeYx6Po-HgZy8Rq+Ih!A9Sr1Kj$BbUt2Ll&DcVv4Nm*FeXw5Oo)GfYy7Qp-Ih#z8Sr0Ji$BaTs1Lk%CbVu3Ml*EdWv5On(FfYx6Po-HgZy8Rq+Ii!A9Ss1Kj$CbUt2Ll&DcVv4Nm*FeXw5Po)GfZy7Qp-Ih#z8Sr0Ji$BaTs2Lk%CcVu3Ml*EdWv5On(FfYx6Pp-HgZz8Rq+Ii!A9Ss1Kj$CbUt2Ml&DcWv4Nm(FeXw5Po)GfZy7Qp+Ih#z9Sr0Jj$BaTs2Lk%CcVu3Mm*EdWw5On(GfYx6Pp- HgZz8Rq+Ji!A9Ts1Kj%CbUt2Ml&DcWv4Nm(FeXw6Po)GgZy7Qp+Ih#z9Sr0Jj$BaTt2Lk%DcVu3Mm*EdWw5On(GfYx6Qp-Hg#z8Rq0Ji!A9Ts1Kj%CbUt3Ml&DdWv4Nn(FeXw6Po)GgZyaUt2Lk