非ST段抬高急性冠脈綜合征介入治療

1、非ST段抬高急性冠脈綜合征介入治療-策略與選擇阜外心血管病醫(yī)院 喬樹賓 ACS住院患者（NSTE-ACS vs STEMI）National Center for Health Statistics. 2001.ACS2.3 million hospital admissions ACS ( 230萬/年 ACS住院患者）UA / NSTEMI1.43 million admissions per year（143萬/年患者占63%）STEMI829,000 admissions per year（82.9萬/年患者占36%）ACS主要發(fā)病機理動脈粥樣硬化斑塊-不穩(wěn)定或破裂血栓形成炎癥細胞少量

2、平滑肌細胞激活的巨噬細胞血栓ACS的病理生理基礎CK- MB or TroponinTroponin elevated or notAdapted from Michael DaviesAdapted from Michael Davies ACS 無持續(xù)ST段抬高 ACS 伴持續(xù)ST段抬高ACS的臨床分型ACSST 段持續(xù)抬高的 ACS無 ST 段抬高的 ACScTnT ( cTnI ) 0.1g/L或CK-MB正常上限的2倍cTnT ( cTnI ) 0.1g/L 或CK-MB正常上限的2倍STEMINSTEMI UA非ST段抬高ACS的治療 抗血小板治療 抗凝治療 抗缺血治療 調脂治療

3、介入治療 冠脈搭橋抗栓不溶栓抗血小板、抗凝PCI ？！診 斷常規(guī)血生化，特別包括Tn T或I監(jiān)測心電ST段的變化超聲心動圖檢查 如需排除主動脈夾層，做MRI； 排除肺栓塞行CT或核素檢查觀察對抗缺血治療的效果評定危險記分評價出血的危險性NSTE-ACS危險分層臨床因素年齡原有基礎的左室功能冠脈解剖糖尿病及腎肺功能異常等其它合并病心絞痛的病史特點 心電圖或動態(tài)心電圖 心肌缺血的表現(xiàn) ST段和T波改變 肌鈣蛋白 反應蛋白 纖維蛋白肽 BNP或NTproBNPNSTE-ACS危險分層方法 -早期CAG的價值早期冠脈造影目的： 病變范圍和分布、狹窄程度和部位、適合何種血管重建術等。早期冠脈造影 - 提

4、高預后分層的可靠性 - 確定治療方案的有效方法： 沒有病變可迅速出院 罪犯病變適合 PCI 者可立即介入治療加快出院 左主干病變、復雜病變伴左室功能不全者迅速 CABG -發(fā)現(xiàn)高危病人，使患者從早期血管重建術中獲益ACC/AHA：治療的選擇（一）有創(chuàng)治療：1.盡管充分藥物治療仍發(fā)生靜息或低水平活動心絞痛；2.TnT或TnI升高；3.新出現(xiàn)的ST壓低；4.HF體征和癥狀或新出現(xiàn)或加重的二尖瓣返流；5.無創(chuàng)檢查有高危的證據(jù)；6.持續(xù)性室速；7.六個月內曾PCI；8.先前CABG；9.危險積分屬高危（TIMI，GRACE）；10.左心室功能降低（LVEF40%）ACC/AHA：治療的選擇（二）保守治

5、療：計分屬低危險（TIMI，GRACE）無高危特征的患者或醫(yī)生選擇2007-ESC介入治療緊急（Urgent）1.患者出現(xiàn)持續(xù)性或反復胸痛，伴有或不伴有ST改變（2mm）或深的倒置T波，抗缺血治療效果不好2.出現(xiàn)心衰臨床癥狀或血流動力學不穩(wěn)定3.致命性心律失常（VF、VT）早期72小時1.Tn T或I 2.動態(tài)ST或T改變（有癥狀或無癥狀）3.糖尿病 4.腎功能異常（GFR60ml/min/1.73m2）5.左心室功能降低（LVEF40%）6.梗塞后心絞痛7.有MI病史8.6個月內行PCI ,有CABG史9.中高GRACE危險記分不做或擇期做無再發(fā)胸痛無心衰的體征無新的ECG改變（就診6-12

6、小時）TnT 或I正常（就診6-12小時）0.20.5125Favors InvasiveFavors ConservativeOdds Ratio Death or MIOR 0.82, P=0.001TrialTIMI 3BVANQWISHMATEFRISC IITACTICSRITA 3TOTALMehta SR et al. JAMA 2005;293:2908-175.1%8.1%27.2%28.0%12.0%8.9%4.3%11.4%4.0%5.3%7.4%10.9%VINO4.8%14.8%InvCons7.4%11.0%Invasive Management of UA/NST

7、EMI Meta-analysis: Death/MI at 17 mo. F/UOverall12.214.4Trials 19999.412.4Troponin +ve10.014.0Troponin ve6.77.4Any Marker +ve14.717.4Any Marker -ve7.78.5Favors InvasiveFavors Conservative0.512TrialInv(%)Cons(%)Odds RatioP value0.0010.820.400.900.0120.820.420.890.0010.690.00010.730.920.99*TIMI 3B, VA

8、NQWISH and MATE FRISC II, TACTICS, VINO, RITA 3Data by troponin status available only in FRISC II, TACTICS, RITA 3Invasive Management of UA/NSTEMI Meta-analysis: SubgroupsMehta SR et al. JAMA 2005;293:2908-17Death or MI at Followup36018090300Probability of Death.04.03.02.010Non-Invasive (n = 1235)In

9、vasive (n = 1222)InvasiveNoninvasive RR (95 % CI) 2.2 %4.0 % 0.56 (0.35 - 0.89) p = 0.018Wallentin, Lancet 2000FRISC-II Mortality at One-Year Invasive Vs. Conservative Management Strategies FRISC II: 5 Year OutcomesEnd pointInvasivestrategy (%)Noninvasive strategy (%)Relative risk (95% CI)Death or M

10、I19.924.50.81 (0.690.95)All-causemortality9.710.10.95 (0.751.21)MI12.917.70.73 (0.600.89)Lagerqvist B. World Congress of Cardiology 2006; September 4, 2006, Barcelona, Spain.FRISC II: 5 Year OutcomesDeath or MI at 5 years in high-, medium-, and low-risk patientsEnd pointInvasivestrategy (%)Noninvasi

11、ve strategy (%)Relative risk (95% CI)Death or MI in high-risk patients(FRISC 47)32.741.60.79 (0.640.97)Death or MI inmedium-riskpatients(FRISC 23)14.620.40.72 (0.551.13)Death or MI in low-riskpatients (FRISC 01)10.38.21.26 (0.662.40)Lagerqvist B. World Congress of Cardiology 2006; September 4, 2006,

12、 Barcelona, Spain.哪種治療最好？（Invasive vs Conservative）Conservative（保守）920 PatientsInvasive（介入）7,018 PatientsTIMI IIIBVANQWISHMATEFRISC IITACTICS-TIMI 18VINORITA-3 TRUCS ISAR-COOL Adapted from Cannon CP. Cardiology. 2002;8(special edition):29-37.Conservative1,674 PatientsRoutine vs Selective InvasiveStr

13、ategies in ACSAdapted from Mehta S, et al. JAMA. 2005;293;2908-2917.Odds Ratio (95% CI)0.11.0OR - 0.8295% CI, 0.72-0.93P 60, ischemic EKG or biomarker AND suitable for revascularizationRANDOMIZE*Early InvasiveCoronary angiography as soon as possible (no later than 24 hours) followed by PCI or CABGDe

14、layed InvasiveCoronary angiography any time 36 hrs followed by PCI or CABGASA, clopidogrel, GP IIb/IIIa antagonist as per routine practice*Center chose randomization ratio 1:1, 1:2 or 2:1 Early: DelayedExcludedContraindication for LMWH or high risk of bleeding or not a suitable candidate for revascu

15、larizationFollow-up at 30 days and 6 monthsOutcomesPrimary Composite of Death, new MI or Stroke at 6 mo.SecondaryComposite of: Death, new MI or refractory ischemiaDeath, new MI, stroke, refractory ischemia or repeat revascularizationStrokeStudy Flow ChartTIMACS Stand AloneN=1,398TIMACSTotalN=3,031TI

16、MACS OASIS 5N=1,633+30 Day and 6 month Follow-up 3,029Lost to Follow-up: 4Recommended Medical TreatmentASA, clopidogrel GP IIb/IIIa inhibitor at discretion of attending physician (especially if pt is not on a thienopyridine)Antithrombin:OASIS 5: Either fondaparinux or enoxaparinTIMACS stand alone: U

17、FH or LMWH or fondaparinux or bivalirudin (investigator discretion)Beta blockerStatinParticipating CountriesNorth America 650South America 442Europe 1065Asia 846Australia 28TIMACS Steering CommitteeA. Avezum BrazilC. Morillo - ColumbiaJ-P. Bassand FranceL. Piegas BrazilW. Boden USAJ. Probstfield USA

18、J. Col BelgiumS. Qiao - ChinaR. Diaz ArgentinaH-J Rupprecht GermanyD. Faxon USAP. G. Steg FranceC. Granger USAJ-F. Tanguay-CanadaC. Joyner - CanadaP. Widimsky Czech RepM. Kenda SloveniaJ. Varigos AustraliaS. Mehta - CanadaS. Yusuf - CanadaT. Moccetti SwitzerlandJ. Zhu ChinaStudy OrganizationCoordina

19、ting Center: PHRI, McMaster University S. Mehta, S. Yusuf, S. Jolly, C. Horsman, S. Chrolavicius, B. MeeksDSMB: P. Sleight (chair), J. Anderson, D. DeMets, D. Johnstone, D. HolmesAdjudication Committee Chair: C. Joyner Coordinator: M. LawrenceCriteria for Crossover from Delayed Group to Early GroupR

20、efractory ischemiaNew MIHemodynamic instabilityCrossover from Early to Delayed: 11.9%Crossover from Delayed to Early: 25% Interventions and TimingEarlyN=1,593DelayedN=1,438Coronary Angiography (%)97.695.5Median time (h iqr)14 (3-21)50 (41-81)PCI (%)59.655.0Median time (h iqr)16 (3-23)52 (41-101)CABG

21、 (%)14.713.6Median time (d iqr)7.7 (4.7-17.4)10.8 (6.7-19.8)Iqr=interquartile rangeBaseline CharacteristicsEarlyN=1,593DelayedN=1,438Age65.165.8% Female34.834.7Diabetes26.527.3Prior MI19.720.9Prior PCI13.814.1Prior CABG7.07.3Prior Stroke7.27.5Ischemic ECG 80.579.9Elevated Biomarker77.276.9In-Hospita

22、l MedicationsEarlyN=1,593DelayedN=1,438ASA98.098.1Thieonopyridine87.286.7Thienopyridine or GP IIb/IIIa inhibitor88.288.4GP IIb/IIIa Inhibitor23.222.5AnticoagulantUFH24.624.6LMWH64.064.6Fondaparinux41.941.3Bivalirudin0.50.4Beta Blocker86.886.9Statin85.084.3Primary and Secondary OutcomesEarlyN=1,593De

23、layedN=1,438HR 95% CIPDeath, MI, Stroke9.711.40.850.68-1.060.15Death, MI, refractory ischemia9.613.10.720.58-0.890.002Death, MI, Stroke, refractory ischemia + repeat intervention16.719.70.840.71-0.990.039Death4.96.00.810.60-1.110.19MI4.85.80.830.61-1.140.25Stroke1.31.40.900.48-1.680.74Ref. Ischemia1

24、.03.30.300.17-0.53= 3 g/dL2.32.6Transfusion 2 U2.22.9Pre-specified SubgroupsOverallAge =65FemaleMaleNo ST deviationST deviationNo elevated markerElevated MarkerGRACE 0-140GRACE =1413031129317361052197615231508668236320709619.76.512.39.79.87.611.710.59.57.714.10.4630.5400.7220.4230.00970.85 ( 0.68 -

25、1.06 )0.98 ( 0.64 - 1.52 )0.83 ( 0.64 - 1.07 )0.77 ( 0.54 - 1.12 )0.89 ( 0.68 - 1.18 )0.88 ( 0.62 - 1.26 )0.81 ( 0.61 - 1.07 )1.00 ( 0.62 - 1.60 )0.81 ( 0.63 - 1.04 )1.14 ( 0.82 - 1.58 )0.65 ( 0.48 - 0.88 )NCharacteristicHR (95% CI)Interaction p-Value0.330.50.71.001.52.03.0Early better Delayed bette

26、r Hazard Ratio (95% CI)Early%11.4 6.514.812.310.98.714.310.511.76.721.6Delayed% GRACE Risk Score: Primary OutcomeHR 1.1495% CI 0.82-1.58P=0.43 HR 0.6595% CI 0.48-0.88P=0.005Interaction P=0.0097Low/Int RiskGRACE Score = 140N=961Death, MI or Stroke at 6 mo.ConclusionsOverall, we found no significant d

27、ifference between an early and a delayed invasive strategy for prevention of death, MI or stroke (primary outcome).However, in the subgroup at highest risk (GRACE score 140), an early invasive strategy was superior to a delayed invasive strategy for prevention of death, MI or strokeThe early invasiv

28、e strategy also had a large impact on reducing the rate of refractory ischemia by 70%.There were no significant differences in major bleeding or other safety concerns between the two strategiesImplicationsMost patients with ACS can be managed safely with either an early or a delayed invasive strateg

29、yIn a subset of patients at highest risk (GRACE score140), early intervention is superior and these patients should be taken to the cath lab as early as possibleIn all other patients, the decision regarding timing of intervention can depend on other factors, such as cath lab availability and economi

30、c considerations.TIMACSAn International Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with Non-ST Segment Elevation Acute Coronary Syndromes 對比非ST段抬高的急性冠狀動脈綜合征患者早期與延遲干預治療的國際隨機研究中國亞組TIMACSAn International Randomized Trial of Early Versus Delayed Invasive Strategies in Patie

31、nts with Non-ST Segment Elevation Acute Coronary Syndromes共有815名患者入選本研究 早期介入組 446名，隨訪率98.4% 延遲介入組 369名，隨訪率98.8% 臨床基線、合并用藥及冠造結果兩組無統(tǒng)計學差異 冠造的平均時間 早期介入組18.4小時 延遲介入組72.6小時 TIMACSAn International Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with Non-ST Segment Elevation Acute C

32、oronary Syndromes180天隨訪主要終點事件（死亡、心梗、卒中） 早期介入組 9.0% 延遲介入組 14.6% （P=0.01） - 死亡 早期介入組 3.6% 延遲介入組 3.3% （P=0.79） - 心梗 早期介入組 5.2% 延遲介入組 10.8% （P=0.002） - 卒中 早期介入組 0.2% 延遲介入組 0.5% （P=0.87）TIMACSAn International Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with Non-ST Segment Ele

33、vation Acute Coronary Syndromes180天隨訪次要終點事件 死亡、心梗、難治性心肌缺血 早期介入組 14.6% 延遲介入組 22.0% （P=0.01） 死亡、心梗、卒中、難治性心肌缺血、再次血運重建 早期介入組 26.7% 延遲介入組 30.4% （P=0.25）TIMACSAn International Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with Non-ST Segment Elevation Acute Coronary Syndromes*P0

34、.05TIMACSAn International Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with Non-ST Segment Elevation Acute Coronary Syndromes30天隨訪主要終點事件（死亡、心梗、卒中） 早期介入組 8.1% 延遲介入組 12.5% （P=0.04） - 死亡 早期介入組 2.9% 延遲介入組 2.2% （P=0.503） - 心梗 早期介入組 5.2% 延遲介入組 10.0% （P=0.01） - 卒中 早期介入組 0% 延遲介入組

35、 0.3% （P=0.45）TIMACSAn International Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with Non-ST Segment Elevation Acute Coronary Syndromes30天隨訪次要終點事件 死亡、心梗、難治性心肌缺血 早期介入組 13.0% 延遲介入組 19.0% （P=0.02） 死亡、心梗、卒中、難治性心肌缺血、再次血運重建 早期介入組 23.5% 延遲介入組 26.6% （P=0.32）TIMACSAn Internationa

36、l Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with Non-ST Segment Elevation Acute Coronary Syndromes*P0.05TIMACSAn International Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with Non-ST Segment Elevation Acute Coronary Syndromes180天隨訪安全性終點-大出血

37、 早期介入組 0.7% 延遲介入組 0.5% （P=1.00） 30天隨訪安全性終點-大出血 早期介入組 0.7% 延遲介入組 0.3% （P=0.75） ESC 指南（一）對于伴有ST段動態(tài)改變頑固性或反復發(fā)作的心絞痛，心衰，惡性心律失?；蜓鲃恿W不穩(wěn)定者應做緊急冠狀動脈造影（I-C）對于具有中高危險特征的患者應做早期冠狀動脈造影（72小時），進行血運重建（PCI或CABG）（I-A）不推薦常規(guī)對沒有中高危險特征的患者進行有創(chuàng)評價（III-C），建議進行能夠誘發(fā)心肌缺血的無創(chuàng)檢查（I-C）ESC血運重建指南（二）不推薦對非顯著病變進行PCI（III-C）選擇BMS或DES時，應仔細認真評估

38、風險-效益比，合并病和是否近期非心臟手術停用雙重抗血小板藥物的可能性（I-C）ESC血運重建（三）造影沒有顯著病變藥物治療造影有顯著病變：單支病變處理罪犯病變；多支：PCI或CABG的選擇應個體化 有些僅處理罪犯病變以后再擇期外科提倡介入術前應用GPIIb/IIIa拮抗劑如計劃搭橋，波立維應停用5天NSTE-ACS不完全或完全”罪犯”血管再血管化治療?Anibal A Damonte,Argenitina.Am J Cardiol.2007,TCT出院及出院后的治療特別強調各種危險因素的控制生活方式的改善規(guī)律服藥NSTEACS介入治療選擇NSTEACS患者的自然轉歸差別很大，危險分層有助于判斷

39、預后和指導治療策略。 介入治療是ACS現(xiàn)代治療整體的一部分。目前更傾向于早期介入干預治療高?；颊?。輔助治療中可以用很多藥物替代，但對于高危患者盡快行心導管檢查比選擇哪個藥物合適更重要。THANKSaLdOgSjVnYq!t*w-z1D4G7JbMeQhTkWoZr$u(x+B2E5H9KcNfRiUmXp#s&v)y0C3F7IaLdPgSjVnYq$t*w-A1D4G8JbNeQhTlWoZr%u(y+B2E6H9KcOfRjUmXp!s&v)z0C3F7IaMdPgSkVnYq$t*x-A1D5G8JbNeQiTlWo#r%u(y+B3E6H9LcOfRjUmYp!s&w)z0C4F7Ja

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42、5H9KcNfRiUlXp#s&v)y0C3F6IaLdPgSjVnYq!t*w-A1D4G8JbMeQhTkWoZr%u(x+B2E5H9KcOfRiUmXp#s&v)z0C3F7IaLdPgSkVnYq$t*w-A1D5G8JbNeQhTlWo#r%u(y+B2E6H9LcOfRjUmXp!s&v)z0C4F7IaMdPgSkVnZq$t*x-A1D5G8KbNeQiTlWo#r%v(y+B3E6H9LcOgRjUmYp!s&w)z1C4F7JaMdPhSkWnZq$u*x-A2D5G8KbNfQiTlXo#r%v(y0B3E6I9LcOgRjVmYp!t&w)z1C4G7JaMePhSk

43、WnZr$u*x+A2D5H8KcNfQiUlXo#s%v)y0B3F6I9LdOgSjVmYq!t&w-z1C4G7JbMePhTkWnZr$u(x+A2E5H8KcNfRiUlXp#s%v)y0C3F6IaLdOgSjVnYq!t*w-z1D4G8JbMeQhTkWoZr%u(x+B2E5H9KcNfRiUmXp#s&v)y0C3F7IaLdPgSjVnYq$t*w-A1D4G8JbNeJbNeQhTlWoZr%u(y+B2E6H9KcOfRjUmXp!s&v)z0C4F7IaMdPgSkVnZq$t*x-A1D5G8KbNeQiTlWo#r%v(y+B3E6H9LcOfRjUmYp!s&

44、w)z0C4F7JaMdPhSkVnZq$u*x-A2D5G8KbNfQiTlXo#r%v(y0B3E6I9LcOgRjVmYp!t&w)z1C4G7JaMePhSkWnZr$u*x+A2D5H8KbNfQiUlXo#s%v(y0B3F6I9LdOgRjVmYq!t&w-z1C4G7JbMePhTkWnZr$u(x+A2E5H8KcNfRiUlXp#s%v)y0C3F6IaLdOgSjVmYq!t*w-z1D4G7JbMeQhTkWoZr$u(x+B2E5H9KcNfRiUmXp#s&v)y0C3F7IaLdPgSjVnYq$t*w-A1D4G8JbNeQhTlWoZr%u(y+B2E6H9K

45、cOfRiUmXp!s&v)z0C3F7IaMdPgSkVnYq$t*x-A1D5G8JbNeQiTlWo#r%u(y+B3E6H9LcOfRjUmYp!s&w)z0C4F7JaMdPhSkVnZq$t*x-A2D5G8KbNeQiTlXo#r%v(y+B3E6I9LcOgRjUmYp!t&w)z1C4F7JaMePhSkWnZq$u*x+A2D5H8KbNfQiUlXo#s%v(y0y0B3F6I9LdOgRjVmYq!t&w-z1C4G7JaMePhTkWnZr$u*x+A2E5H8KcNfQiUlXp#s%v)y0B3F6IaLdOgSjVmYq!t*w-z1D4G7JbMeQhTkWo

46、Zr$u(x+B2E5H9KcNfRiUlXp#s&v)y0C3F6IaLdPgSjVnYq!t*w-A1D4G8JbMeQhTlWoZr%u(x+B2E6H9KcOfRiUmXp!s&v)z0C3F7IaMdPgSkVnYq$t*w-A1D5G8JbNeQhTlWo#r%u(y+B2E6H9LcOfRjUmXp!s&w)z0C4F7IaMdPhSkVnZq$t*x-A2D5G8KbNeQiTlXo#r%v(y+B3E6I9LcOgRjUmYp!s&w)z1C4F7JaMdPhSkWnZq$u*x-A2D5H8KbNfQiTlXo#s%v(y0B3E6I9LdOgRjVmYp!t&w-z1C4

47、G7JaMePhTkWnZr$u*x+A2D5H8KcNfQiUlXo#s%v)y0B3F6I9LdOdOgSjVmYq!t&w-z1D4G7JbMePhTkWoZr$u(x+A2E5H9KcNfRiUlXp#s&v)y0C3F6IaLdPgSjVnYq!t*w-A1D4G8JbMeQhTkWoZr%u(x+B2E5H9KcOfRiUmXp#s&v)z0C3F7IaLdPgSkVnYq$t*w-A1D5G8JbNeQhTlWo#r%u(y+B2E6H9LcOfRjUmXp!s&v)z0C4F7IaMdPgSkVnZq$t*x-A1D5G8KbNeQiTlWo#r%v(y+B3E6H9LcOgR

48、jUmYp!s&w)z1C4F7JaMdPhSkWnZq$u*x-A2D5H8KbNfQiTlXo#r%v(y0B3E6I9LcOgRjVmYp!t&w)z1C4G7JaMePhSkWnZr$u*x+A2D5H8KcNfQiUlXo#s%v)y0B3F6I9LdOgSgSjVmYq!t&w-z1D4G7JbMePhTkWoZr$u(x+A2E5H8KcNfRiUlXp#s%v)y0C3F6IaLdOgSjVnYq!t*w-z1D4G8JbMeQhTkWoZr%u(x+B2E5H9KcOfRiUmXp#s&v)z0C3F7IaLdPgSjVnYq$t*w-A1D4G8JbNeQhTlWoZr%u

49、(y+B2E6H9KcOfRjUmXp!s&v)z0C4F7IaMdPgSkVnZq$t*x-A1D5G8KbNeQiTlWo#r%u(y+B3E6H9LcOfRjUmYp!s&w)z0C4F7JaMdPhSkVnZq$u*x-A2D5G8KbNfQiTlXo#r%v(y0B3E6I9LcOgRjVmYp!t&w)z1C4G7JaMePhSkWnWnZr$u*x+A2D5H8KbNfQiUlXo#s%v(y0B3F6I9LdOgRjVmYq!t&w-z1C4G7JbMePhTkWnZr$u(x+A2E5H8KcNfRiUlXp#s%v)y0C3F6IaLdOgSjVmYq!t*w-z1D4G7JbMeQhTkWoZr$u(x+B2E5H9KcNfRiUmXp#s&v)y0C3F7IaLdPgSjVnYq$t*w-A1D4G8JbNeQhTlWoZr%u(y+B2E6H9KcOfRiUmXp!s&v)z0C3F7IaMdPgSkVnYq$t*x-A1D5G8JbNeQiTlWo#r%u(