CardioSource WorldNews - Page 36

LIVE COURSES2017

April 28 – 29
Puerto Rico Chapter of the American College of Cardiology
Cond . Medical Center Plaza Calle 3 SE # 1051 , Ofic . LC-10 Urb . La Riviera San Juan , Puerto Rico
RANEXA ® ( ranolazine )
Brief summary of full Prescribing Information . Please see full Prescribing Information . Rx Only .
INDICATIONS AND USAGE : RANEXA ® is indicated for the treatment of chronic angina . RANEXA may be used with beta-blockers , nitrates , calcium channel blockers , anti-platelet therapy , lipid-lowering therapy , ACE inhibitors , and angiotensin receptor blockers .
DOSAGE AND ADMINISTRATION : Initiate RANEXA dosing at 500 mg twice daily ( BID ) and increase to 1000 mg BID , as needed , based on clinical symptoms . Take RANEXA with or without meals . Swallow RANEXA tablets whole ; do not crush , break , or chew . The maximum recommended daily dose of RANEXA is 1000 mg BID . If a dose of RANEXA is missed , take the prescribed dose at the next scheduled time ; do not double the next dose .
Dose Modification : Dose adjustments may be needed when RANEXA is taken in combination with certain other drugs . Limit the maximum dose of RANEXA to 500 mg BID in patients on moderate CYP3A inhibitors such as diltiazem , verapamil , and erythromycin . Use of P-gp inhibitors , such as cyclosporine , may increase exposure to RANEXA . Titrate RANEXA based on clinical response .
CONTRAINDICATIONS :
• Taking strong inhibitors of CYP3A • Taking inducers of CYP3A • With liver cirrhosis WARNINGS AND PRECAUTIONS : QT Interval Prolongation : Ranolazine blocks I Kr and prolongs the QTc interval in a dose-related manner . Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death . However , there is little experience with high doses (> 1000 mg BID ) or exposure , other QT-prolonging drugs , potassium channel variants resulting in a long QT interval , in patients with a family history of ( or congenital ) long QT syndrome , or in patients with known acquired QT interval prolongation .
Renal Failure : Acute renal failure has been observed in some patients with severe renal impairment ( creatinine clearance [ CrCL ]< 30 mL / min ) while taking RANEXA . If acute renal failure develops ( e . g ., marked increase in serum creatinine ( SCr ) associated with an increase in blood urea nitrogen [ BUN ]), discontinue RANEXA and treat appropriately . Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment ( CrCL < 60 mL / min ) for increases in SCr accompanied by an increase in BUN .
ADVERSE REACTIONS : Adverse Reactions from Clinical Trial Experience : A total of 2018 patients with chronic angina were treated with ranolazine in controlled clinical trials . Of the patients treated with RANEXA , 1026 were enrolled in three double-blind , placebo-controlled , randomized studies of up to 12 weeks ’ duration . In addition , upon study completion , 1251 patients received treatment with RANEXA in open-label , long-term studies ; 1227 patients for > 1 year , 613 for > 2 years , 531 for > 3 years , and 326 for > 4 years . At recommended doses , about 6 % of patients discontinued treatment with RANEXA because of an adverse event in controlled studies in angina patients compared to about 3 % on placebo . The most common adverse events that led to discontinuation more frequently on RANEXA than placebo were dizziness ( 1.3 % versus 0.1 %), nausea ( 1 % versus 0 %), asthenia , constipation , and headache ( each about 0.5 % versus 0 %). Doses above 1000 mg BID are poorly tolerated . In controlled clinical trials of angina patients , the most frequently reported treatment-emergent adverse reactions (> 4 % and more common on RANEXA than on placebo ) were dizziness ( 6.2 %), headache ( 5.5 %), constipation ( 4.5 %), and nausea ( 4.4 %). Dizziness may be dose-related . The following additional adverse reactions occurred at an incidence of 0.5 to 4.0 % in patients treated with RANEXA and were more frequent than the incidence observed in placebo-treated patients :
Cardiac Disorders – bradycardia , palpitations Ear and Labyrinth Disorders – tinnitus , vertigo Eye Disorders – blurred vision Gastrointestinal Disorders – abdominal pain , dry mouth , vomiting , dyspepsia General Disorders and Administrative Site Adverse Events – asthenia , peripheral edema Metabolism and Nutrition Disorders – anorexia Nervous System Disorders – syncope ( vasovagal ) Psychiatric Disorders – confusional state Renal and Urinary Disorders – hematuria Respiratory , Thoracic , and Mediastinal Disorders – dyspnea Skin and Subcutaneous Tissue Disorders – hyperhidrosis Vascular Disorders – hypotension , orthostatic hypotension
Other (< 0.5 %) but potentially medically important adverse reactions observed more frequently with RANEXA than placebo treatment in all controlled studies included : angioedema , renal failure , eosinophilia , chromaturia , blood urea increased , hypoesthesia , paresthesia , tremor , pulmonary fibrosis , thrombocytopenia , leukopenia , and pancytopenia . A large clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating a benefit for RANEXA , but there was no apparent proarrhythmic effect in these high-risk patients .
Laboratory Abnormalities
RANEXA produces elevations of SCr by 0.1 mg / dL , regardless of previous renal function , likely because of inhibition of creatinine ’ s tubular secretion . In general , the elevation has a rapid onset , shows no signs of progression during long-term therapy , is reversible after discontinuation of RANEXA , and is not accompanied by changes in BUN . In healthy volunteers , RANEXA 1000 mg BID had no effect upon the glomerular filtration rate . More marked and progressive increases in SCr , associated with increases in BUN or potassium , indicating acute renal failure , have been reported after initiation of RANEXA in patients with severe renal impairment .
Postmarketing Experience
Nervous System Disorders - Tremor , paresthesia , abnormal coordination , and other serious neurologic adverse events have been reported to occur , sometimes concurrently , in patients taking ranolazine . The onset of events was often associated with an increase in ranolazine dose or exposure . Many patients reported symptom resolution following drug discontinuation or dose decrease .
Metabolism and Nutrition Disorders – Cases of hypoglycemia have been reported in diabetic patients on anti-diabetic medication . Psychiatric Disorders – hallucination Renal and Urinary Disorders – dysuria , urinary retention Skin and Subcutaneous Tissue Disorders – angioedema , pruritus , rash
DRUG INTERACTIONS : Effects of Other Drugs on Ranolazine
Strong CYP3A Inhibitors : Do not use RANEXA with strong CYP3A inhibitors , including ketoconazole , itraconazole , clarithromycin , nefazodone , nelfinavir , ritonavir , indinavir , and saquinavir . Moderate CYP3A Inhibitors : Limit the dose of RANEXA to 500 mg BID in patients on moderate CYP3A inhibitors , including diltiazem , verapamil , erythromycin , fluconazole , and grapefruit juice or grapefruit-containing products . P-gp Inhibitors : Concomitant use of RANEXA and P-gp inhibitors , such as cyclosporine , may result in increases in ranolazine concentrations . Titrate RANEXA based on clinical response . CYP3A Inducers : Do not use RANEXA with CYP3A inducers such as rifampin , rifabutin , rifapentine , phenobarbital , phenytoin , carbamazepine , and St . John ’ s wort .
Effects of Ranolazine on Other Drugs
Drugs Metabolized by CYP3A : Limit the dose of simvastatin in patients on any dose of RANEXA to 20 mg once daily , when ranolazine is co-administered . Dose adjustment of other sensitive CYP3A substrates ( e . g ., lovastatin ) and CYP3A substrates with a narrow therapeutic range ( e . g ., cyclosporine , tacrolimus , sirolimus ) may be required as RANEXA may increase plasma concentrations of these drugs . Drugs Transported by P-gp : Concomitant use of ranolazine and digoxin results in increased exposure to digoxin . The dose of digoxin may have to be adjusted . Drugs Metabolized by CYP2D6 : The exposure to CYP2D6 substrates , such as tricyclic antidepressants and antipsychotics , may be increased during co-administration with RANEXA , and lower doses of these drugs may be required . Drugs Transported by OCT2 : In subjects with type 2 diabetes mellitus , concomitant use of RANEXA 1000 mg BID and metformin results in increased plasma levels of metformin . When RANEXA 1000 mg BID is co-administered with metformin , metformin dose should not exceed 1700 mg / day . Monitor blood glucose levels and risks associated with high exposures of metformin . Metformin exposure was not significantly increased when given with RANEXA 500 mg BID .
USE IN SPECIFIC POPULATIONS : Pregnancy : There are no available data on RANEXA use in pregnant women to inform any drug-associated risks . Embryofetal toxicity studies were conducted in rats and rabbits orally administered ranolazine during organogenesis . In rats , decreased fetal weight and reduced ossification were observed at doses ( corresponding to 4-fold the AUC for the maximum recommended human dose [ MRHD ]) that caused maternal weight loss . No adverse fetal effects were observed in either species exposed ( AUC ) to ranolazine at exposures ( AUC ) equal to the MRHD . Lactation : There are no data on the presence of ranolazine in human milk , the effects on the breastfed infant , or the effects on milk production . However , ranolazine is present in rat milk . The developmental and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for RANEXA and any potential adverse effects on the breastfed infant from RANEXA or from the underlying maternal condition . Pediatric Use : Safety and effectiveness have not been established in pediatric patients . Geriatric Use : Of the chronic angina patients treated with RANEXA in controlled studies , 496 ( 48 %) were ≥65 years of age , and 114 ( 11 %) were ≥75 years of age . No overall differences in efficacy were observed between older and younger patients . There were no differences in safety for patients ≥65 years compared to younger patients , but patients ≥75 years of age on RANEXA , compared to placebo , had a higher incidence of adverse events , serious adverse events , and drug discontinuations due to adverse events . In general , dose selection for an elderly patient should usually start at the low end of the dosing range , reflecting the greater frequency of decreased hepatic , renal , or cardiac function , and of concomitant disease , or other drug therapy . Use in Patients with Hepatic Impairment : RANEXA is contraindicated in patients with liver cirrhosis . In a study of cirrhotic patients , the C max of ranolazine was increased 30 % in cirrhotic patients with mild ( Child-Pugh Class A ) hepatic impairment , but increased 80 % in cirrhotic patients with moderate ( Child-Pugh Class B ) hepatic impairment compared to patients without hepatic impairment . This increase was not enough to account for the 3-fold increase in QT prolongation seen in cirrhotic patients with mild to moderate hepatic impairment . Use in Patients with Renal Impairment : A pharmacokinetic study of RANEXA in subjects with severe renal impairment ( CrCL < 30 mL / min ) was stopped when 2 of 4 subjects developed acute renal failure after receiving RANEXA 500 mg BID for 5 days ( lead-in phase ) followed by 1000 mg BID ( 1 dose in one subject and 11 doses in the other ). Increases in creatinine , BUN , and potassium were observed in 3 subjects during the 500 mg lead-in phase . One subject required hemodialysis , while the other 2 subjects improved upon drug discontinuation . Monitor renal function periodically in patients with moderate to severe renal impairment . Discontinue RANEXA if acute renal failure develops . In a separate study , C max was increased between 40 % and 50 % in patients with mild , moderate , or severe renal impairment compared to patients with no renal impairment , suggesting a similar increase in exposure in patients with renal failure independent of the degree of impairment . The pharmacokinetics of ranolazine has not been assessed in patients on dialysis . Use in Patients with Heart Failure : Heart failure ( NYHA Class I to IV ) had no significant effect on ranolazine pharmacokinetics . RANEXA had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA Class I to IV . No dose adjustment of RANEXA is required in patients with heart failure . Use in Patients with Diabetes Mellitus : A population pharmacokinetic evaluation of data from angina patients and healthy subjects showed no effect of diabetes on ranolazine pharmacokinetics . No dose adjustment is required in patients with diabetes . RANEXA produces small reductions in HbA1c in patients with diabetes , the clinical significance of which is unknown . RANEXA should not be considered a treatment for diabetes .
© 2016 Gilead Sciences , Inc All rights reserved . REF11943 05 / 16 © 2016 Gilead Sciences , Inc All rights reserved . RANP0417 07 / 16
April 29
Oklahoma Chapter Annual Meeting 2017
Samis Education Center University of Oklahoma Oklahoma City , OK
June 2 – 4
Alabama Chapter Annual Meeting 2017
Sandestin Golf & Beach Resort Destin , FL
August 18 – 20
Florida Chapter Annual Meeting 2017
Disney ’ s Contemporary Resort Lake Buena Vista , FL
September 29 – October 1
SC / NC Chapters ACC 23rd Annual Joint Meeting
Kiawah Island Golf Resort Kiawah Island , SC
October 14 – 21
Ohio Chapter Annual Meeting 2017
Columbus Hilton at Easton Columbus , OH
LIVE COURSES 2017 April 28–29 April 29 Puerto Rico Chapter of the American College of Cardiology Oklahoma Chapter Annual Meeting 2017 Samis Education Center University of Oklahoma Oklahoma City, OK Cond. Medical Center Plaza Calle 3 SE #1051, Ofic. LC-10 Urb. La Riviera San Juan, Puerto Rico June 2–4 Alabama Chapter Annual Meeting 2017 RANEXA® (ranolazine) Brief summary of full Prescribing Information. Please see full Prescribing Information. Rx Only. INDICATIONS AND USAGE: RANEXA® is indicated for the treatment of chronic angina. RANEXA may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. DOSAGE AND ADMINISTRATION: Initiate RANEXA dosing at 500 mg twice daily (BID) and increase to 1000 mg BID, as needed, based on clinical symptoms. Take RANEXA with or without meals. Swallow RANEXA tablets whole; do not crush, break, or chew. The maximum recommended daily dose of RANEXA is 1000 mg BID. If a dose of RANEXA is missed, take the prescribed dose at the next scheduled time; do not double the next dose. Dose Modification: Dose adjustments may be needed when RANEXA is taken in combination with certain other drugs. Limit the maximum dose of RANEXA to 500 mg BID in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of P-gp inhibitors, such as cyclosporine, may increase exposure to RANEXA. Titrate RANEXA based on clinical response. CONTRAINDICATIONS: • Taking strong inhibitors of CYP3A • Taking inducers of CYP3A • With liver cirrhosis WARNINGS AND PRECAUTIONS: QT Interval Prolongation: Ranolazine blocks IKr and prolongs the QTc interval in a dose-related manner. Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death. However, there is little experience with high doses (>1000 mg BID) or exposure, other QT-prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation. Renal Failure: Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL]<30 mL/min) while taking RANEXA. If acute renal failure develops (e.g., marked increase in serum creatinine (SCr) associated with an increase in blood urea nitrogen [BUN]), discontinue RANEXA and treat appropriately. Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL<60 mL/min) for increases in SCr accompanied by an increase in BUN. ADVERSE REACTIONS: Adverse Reactions from Clinical Trial Experience: A total of 2018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with RANEXA, 1026 were enrolled in three double-blind, placebo-controlled, randomized studies of up to 12 weeks’ duration. In addition, upon study completion, 1251 patients received treatment with RANEXA in open-label, long-term studies; 1227 patients for >1 year, 613 for >2 years, 531 for >3 years, and 326 for >4 years. At recommended doses, about 6% of patients discontinued treatment with RANEXA because of an adverse event in controlled studies in angina patients compared to about 3% on placebo. The most common adverse events that led to discontinuation more frequently on RANEXA than placebo were dizziness (1.3% versus 0.1%), nausea (1% versus 0%), asthenia, constipation, and headache (each about 0.5% versus 0%). Doses above 1000 mg BID are poorly tolerated. In controlled clinical trials of angina patients, the most frequently reported treatment-emergent adverse reactions (>4% and more common on RANEXA than on placebo) were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). Dizziness may be dose-related. The following additional adverse reactions occurred at an incidence of 0.5 to 4.0% in patients treated with RANEXA and were more frequent than the incidence observed in placebo-treated patients: Cardiac Disorders – bradycardia, palpitations Ear and Labyrinth Disorders – tinnitus, vertigo Eye Disorders – blurred vision Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting, dyspepsia General Disorders and Administrative Site Adverse Events – asthenia, peripheral edema Metabolism and Nutrition Disorders – anorexia Nervous System Disorders – syncope (vasovagal) Psychiatric Disorders – confusional state Renal and Urinary Disorders – hematuria Respiratory, Thoracic, and Mediastinal Disorders – dyspnea Skin and Subcutaneous Tissue Disorders – hyperhidrosis Vascular Disorders – hypotension, orthostatic hypotension Other (<0.5%) but potentially medically important adverse reactions observed more frequently with RANEXA than placebo treatment in all controlled studies included: angioedema, renal failure, eosinophilia, chromaturia, blood urea increased, hypoesthesia, paresthesia, tremor, pulmonary fibrosis, thrombocytopenia, leukopenia, and pancytopenia. A large clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating a benefit for RANEXA, but there was no apparent proarrhythmic effect in these high-risk patients. Laboratory Abnormalities RANEXA produces elevations of SCr by 0.1 mg/dL, regardless of previous renal function, likely because of inhibition of creatinine’s tubular secretion. In general, the elevation has a rapid onset, shows no signs of progression during long-term therapy, is reversible after discontinuation of RANEXA, and is not accompanied by changes in BUN. In healthy volunteers, RANEXA 1000 mg BID had no effect upon the glomerular filtration rate. More marked and progressive increases in SCr, associated with increases in BUN or potassium, indicating acute renal failure, have been reported after initiation of RANEXA in patients with severe renal impairment. 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