Clinical trial NCT02918019
Conditions: Asthma
Sponsor: Hoffmann-La Roche
Start date: 2016-09-20; Completion date: 2019-07-26
Enrollment: 517 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase IIb, randomized, placebo-controlled, double-blind, multicenter, multi-arm study which will evaluate efficacy, safety, and pharmacokinetic of MSTT1041A compared with placebo as add-on therapy in participants with severe, uncontrolled asthma who are receiving medium- or high-dose inhaled corticosteroid (ICS) therapy and at least one of the following additional controller medications: long-acting beta-agonists (LABA), leukotriene modifier (LTM), long-acting muscarinic antagonist (LAMA), or long-acting theophylline preparation. The total duration of this study for each participant is approximately 70 weeks including screening, run-in, treatment, and follow-up.

Detailed description:

Arms: arm 1: Participants will receive MSTT1041A 210 milligrams (mg), subcutaneously every 4 weeks from randomization through Week 50. arm 2: Participants will receive MSTT1041A 490 mg, subcutaneously every 4 weeks from randomization through Week 50. arm 3: Participants will receive MSTT1041A 70 mg, subcutaneously every 4 weeks from randomization through Week 50. arm 4: Participants will receive placebo matched with MSTT1041A, subcutaneously every 4 weeks from randomization through Week 50.
Interventions: intervention 1: MSTT1041A intervention 2: Placebo
Intervention descriptions: intervention 1: MSTT1041A will be administered as subcutaneous injections. intervention 2: Placebo matched with MSTT1041A.

Protocol documents:
Prot_000.pdf: 
Official Title: A Phase IIB, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Dose-
Ranging Study to Assess the Efficacy and Safety of MSTT1041A in Patients with Uncontrolled 
Severe Asthma 
NCT Number: NCT02918019 
Document Date: Protocol Version 4: 23 January 2019 




 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
   
 
  
   
 
 
  
  
 
  
 
  
 
 
 
  
  
 
 
 
 
  
  
  
  
 
   
   
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
   
 
 
  
   
 
 
  
 
 
 
 
 
  
 
 
 
 
 
   
  
 
  
 
 
   
 
   
  
 
  
 
 
 
 
  
 
 
 
   
 
 
 
 
   
 
  
  
 
  
 
   
 
 
  
  
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
  
   
 
 
  
   
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
   
 
  
 
  
 
  
 
  
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
  
  
 
 
  
 
 
   
  
 
  
 
 
 
   
 
 
 
  
 
 
  
 
 
 
  
 
 
 
   
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
  
 
 
 
 
   
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
  
 
 
  
 
  
 
  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
   
  
 
  
 
 
  
 
 
 
 
 
  
 
  
 
 
  
 
  
 
  
 
 
  
 
  
 
 
  
 
  
 
 
 
 
  
 
  
 
 
  
 
  
 
 
 
  
 
  
 
 
  
 
  
 
 
  
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
   
 
 
  
 
 
  
   
 
 
 
  
 
 
 
  
 
 
  
   
 
 
  
 
 
  
   
 
 
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
  
 
   
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
  
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
   
 
 
 
  
 
   
 
 
  
 
 
  
 
 
 
  
 
 
  
 
  
   
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
 
 
  
 
 
  
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
  
 
  
 
  
  
 
 
 
 
  
 
  
   
 
  
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
   
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
  
  
 
 
  
 
  
  
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
  
  
  
 
  
 
  
 
 
  
 
 
 
 
  
  
  
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
  
 
 
  
 
  
 
  
 
 
  
 
 
  
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
  
 
  
  
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
  
 
  
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
  
 
 
  
 
 
  
 
 
 
  
 
 
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
  
  
 
 
 
 
 
 
  
  
 
  
 
 
  
  
  
 
  
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
  
 
 
 
 
  
  
 
 
 
  
 
  
 
  
 
 
  
 
  
 
  
  
 
 
 
  
  
 
 
  
 
 
 
 
  
  
 
 
 
  
 
   
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
  
 
  
 
 
 
  
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
  
 
  
 
 
 
  
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
  
  
 
 
  
   
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
   
 
 
   
 
  
 
  
 
 
  
 
 
 
 
    
 
  
 
 
 
 
 
 
 
    
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
  
 
 
 
 
  
  
 
  
 
 
 
  
 
 
 
 
 
  
  
 
 
 
  
   
 
 
 
  
  
 
  
  
 
 
  
 
   
 
 
 
  
   
 
 
  
 
  
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
   
 
 
  
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
   
  
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
  
 
  
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
  
  
 
 
  
 
 
 
 
 
  
  
 
 
  
 
 
 
 
  
  
 
  
  
 
 
  
 
    
 
 
  
  
 
  
  
 
 
  
 
   
 
 
 
  
  
 
 
 
  
 
 
 
  
 
 
   
 
 
  
  
 
  
 
 
 
 
 
   
 
  
 
  
 
 
 
 
 
  
 
   
 
 
 
 
 
  
 
 
  
 
 
 
 
  
   
 
 
 
 
   
   
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
   
 
 
  
 
 
 
  
   
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
  
  
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
   
 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
  
 
  
 
 
 
  
 
 
 
 
  
 
 
   
 
  
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
  
 
 
  
 
   
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
  
 
 
 
  
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
   
 
 
 
 
 
   
   
 
 
  
 
   
 
 
   
 
 
 
   
 
 
 
 
 
   
  
 
 
  
 
 
   
 
  
 
 
 
  
  
   
 
  
 
 
  
     
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
    
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
   
 
 
  
   
 
   
 
 
 
  
 
   
  
 
  
 
  
  
 
    
 
 
 
 
  
  
 
   
 
 
 
 
 
 
 
 
   
 
  
 
 
 
  
  
  
  
 
  
 
   
 
 
 
  
 
 
  
 
  
   
 
 
  
 
 
 
 
  
 
  
  
  
 
 
   
 
 
 
 
 
 
 
    
  
 
 
 
 
 
  
 
 
   
   
 
  
 
  
  
 
 
  
   
   
 
  
 
 
  
   
  
   
  
 
 
  
 
 
   
  
 
   
 
 
 
  
   
  
 
   
 
  
 
 
  
 
   
  
 
 
  
 
 
 
 
 
 
 
  
  
 
  
 
  
 
   
 
 
  
  
  
 
 
 
 
  
  
  
 
 
  
 
   
  
  
 
   
 
 
  
  
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
  
 
 
  
 
 
   
  
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
   
  
 
 
 
 
 
 
  
  
   
 
 
 
  
  
 
 
  
  
  
 
 
  
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
 
 
 
   
   
 
 
  
   
 
 
 
 
 
 
 
 
  
   
 
 
 
 
  
 
   
  
   
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
 
   
 
 
 
 
 
 
  
 
  
     
 
 
 
 
   
  
 
  
 
 
 
 
   
 
 
  
   
 
  
 
  
 
 
 
 
 
    
 
  
 
  
 
  
 
  
  
  
 
   
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
   
 
  
 
  
 
  
   
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
   
 
  
  
 
  
 
 
 
 
  
 
 
 
 
  
  
  
  
 
 
  
 
   
 
  
   
 
  
   
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
   
  
 
 
 
 
  
 
 
   
 
  
 
  
 
   
 
  
 
   
 
  
 
 
 
 
 
 
 
   
 
 
 
 
   
 
 
  
 
 
   
 
 
 
   
 
 
 
 
  
 
  
 
  
 
 
 
 
  
 
   
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
    
   
 
 
 
 
  
 
    
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
     
 
 
   
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
    
 
 
   
 
 
  
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
   
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
  
  
 
 
  
 
     
  
 
 
   
  
 
  
 
  
 
 
  
    
 
  
  
 
 
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
   
  
 
 
 
  
 
 
 
   
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
  
  
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
  
  
 
  
 
 
   
  
 
  
 
  
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
   
  
 
 
 
  
 
 
 
   
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
  
   
 
 
 
  
  
   
 
 
 
 
 
    
 
   
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
  
  
  
 
  
 
 
 
  
   
 
 
 
 
 
   
 
   
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
   
 
 
 
  
 
  
  
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
  
  
   
 


 
 
 
  
 
 
     
 
 
 
 
 
 
  
  
  
  
 
 
  
  
  
  
 
  
  
 
 
 
  
 
 
 
 
 
  
 
   
 
 
 
 
   
 
 
  
 
  
  
 
  
 
  
 
 
 
    
  
  
 
 
  
  
 
  
   
 
  
   
 
  
  
  
 
  
  
  
 
  
  
 
 
 
 
  
  
 
 
  
   
 
  
   
 
  
  
  
   
   
   
  
   
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
  
   
  
  
  
  
 
  
  
 
 
 
 
   
 
  
   
 
  
  
 
 
   
 
 
 
 
   
 
 
  
 
 
  
  
   
 
 
 
  
  
  
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
  
 
  
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
  
   
 
   
   
 
 
 
 
 
 
  
 
  
  
  
  
  
 
   
   
  
  
 
  
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
  
 
 
 
 
  
 
  
   
  
 
 
 
 
  
 
 
 
  
    
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
  
  
  
 
  
  
 
  
 
  
 
 
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
  
 
  
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
   
 
 
 
  
  
 
 
 
 
  
 
  
 
  
 
   
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
   
 
 
 
  
 
 
  
 
  
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
  
  
 
    
 
 
 
 
 
  
  
 
  
 
   
 
  
 
 
  
    
 
  
   
 
 
 
 
 
   
  
  
 
 
 
 
  
   
 
 
  
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
 
    
  
    
 
  
 
  
 
 
 
  
 
 
 
  
  
  
  
 
  
 
 
 
 
 
 
 
    
 
  
 
 
 
   
  
  
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
   
   
 
  
 
 
 
 
 
 
  
 
 
  
 
   
 
 
  
 
 
  
 
  
 
 
  
 
 
  
 
  
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
    
  
 
 
  
  
 
 
 
    
  
  
 
 
  
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
   
  
 
 
 
 
 
  
  
  
  
 
  
 
  
 
  
 
 
 
  
  
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
  
   


 
 
 
  
 
 
     
 
 
 
 
 
 
  
 
  
   
 
  
 
  
  
 
 
  
 
  
 
  
 
 
 
 
  
  
 
 
 
 
  
 
  
  
  
 
 
 
 
    
 
  
 
  
 
  
 
  
 
 
  
 
 
 
 
 
 
  
 
  
  
 
 
  
 
  
 
 
  
 
 
 
   
 
 
 
 
  
 
 
  
  
 
  
 
 
  
   
   
  
 
 
  
 
  
 
  
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
  
 
  
   
  
 
 
 
 
 
 
 
  
 
 
  
   
 
 
  
 
  
 
  
 
  
 
  
 
 
  
 
 
 
 
  
 
 
  
 
  
 
  
 
  
 
  
  
 
  
   
 
 
   
 
 
 
  
 
  
 
  
 
  
 
  
 
 
 
 
   
 
  
 
  
 
 
 
 
 
 
 
 
   
 
 
  
 
  
  
  
 
 
 
 
 
  
   
 
 
 
 
  
  
  
 
   
 
 
 
  
 
  
  
 
 
  
 
 
 
  
 
 
  
 
 
  
  
 
  
 
  
 
 
 
   
 
 
 
 
 
 
  
  
 
  
  
  
 
  
 
 
 
   
 
 
 
 
 
 
  
 
 
  
  
 
  
 
 
  
   
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
  
   
 
 
 
  
 
  
  
 
 
  
 
 
  
   
 
  
   
 
  
 
   
 


 
 
 
  
 
 
     
 
 
 
 
 
 
  
 
  
   
 
 
 
   
 
 
   
 
 
  
 
 
 
  
 
   
 
 
 
     
 
 
 
 
 
 
 
   
 
 
 
 
 
  
    
  
 
  
 
 
 
   
 
 
 
  
  
    
 
  
 
 
 
 
 
 
  
  
 
 
   
 
 
  
 
 
 
 
  
   
  
 
  
 
  
 
 
  
  
  
 
 
 
   
 
  
 
   
  
 
 
  
 
  
   
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
  
  
 
 
  
 
  
 
  
  
 
 
 
 
 
 
 
  
 
 
 
   
 
 
   
 
   
   
  
   
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
   
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
  
 
 
   
 
   
 
  
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
   
 
  
 
 
 
  
 
 
   
   
 
   
  
 
 
  
 
 
 
 
 
 
 
  
   
  
 
 
 
 
  
 
 
  
 
  
 
  
   
 
  
 
 
 
 
  
  
  
 
  
 
   
  
 
 
  
  
  
   
 
  
 
 
  
 
 
  
 
  
  
 
  
 
 
  
 
 
 
 
 
 
 
  
  
 
  
 
   
  
 
 
  
  
  
   
 
  
 
 
  
 
 
  
 
  
  
 
 
 
 
 
   
 
 
 
   
   
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
   
  
  
   
 
 
 
 
 
 
  
 
  
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
 
  
 
   
 
 
 
 
  
 
  
 
 
  
 
 
  
   
 
  
 
 
 
 
 
   
 
 
 
  
 
 
  
 
 
   
 
  
 
 
 
  
   
 
 
 
 
  
 
 
   
  
 
 
 
 
  
   
  
 
 
  
 
 
   
  
 
   
 
 
 
  
   
  
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
  
  
  
  
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
   
  
 
 
  
 
 
 
 
  
   
  
  
  
 
  
  
 
  
 
 
  
 
 
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
   
   
 
 
 
 
   
  
 
  
 
 
   
   
   
 
  
 
  
 
  
  
 
 
 
 
  
 
 
 
 
   
   
   
 
  
   
 
   
   
 
  
 
 
  
 
 
  
 
 
   
   
   
 
 
  
  
 
 
  
  
 
  
 
  
  
 
  
 
 
 
 
   
   
   
  
 
   
   
 
  
  
 
   
  
 
 
  
  
  
 
 
 
 
  
 
   
  
  
 
  
  
 
   
 
 
 
 
 
  
 
  
 
  
  
  
 
 
  
   
 
    
 
 
 
 
 
  
 
   
 
   
  
  
 
 
  
 
  
   
 
 
 
 
   
   
   
  
   
   
 
  
  
 
  
  
   
 
 
  
 
  
 
 
    
 
  
 
 
 
 
 
 
 
  
  
  
  
 
  
 
  
  
  
 
  
   
 
   
 
 
 
 
  
  
  
   
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
  
 
  
 
   
 
 
   
 
 
 
 
 
 
 
  
  
   
 
  
 
  
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
  
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
   
 
 
  
 
 
 
   
 
   
 
 
  
 
 
 
 
 
 
  
  
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
  
  
 
 
  
 
 
 
   
 
  
  
 
 
 
 
 
   
 
 
 
 
 
 
  
  
  
 
 
 
 
  
  
 
 
   
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
  
   
 
 
 
 
 
   
 
  
 
 
 
   
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
   
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
   
 
 
 
 
   
 
  
 
 
  
 
  
  
  
 
 
   
  
 
 
 
   
  
 
 
 
 
   
 
  
  
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
   
  
   
  
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
  
  
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
  
  
 
 
 
 
  
 
  
 
 
 
 
 
 
   
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
   
  
  
 
 
 
  
  
 
  
 
 
 
 
  
 
 
 
   
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
   
 
   
 
   
 
   
  
  
 
  
 
 
 
 
 
 
 
  
 
   
 
 
 
 
  
 
 
 
  
  
 
 
 
  
 
  
 
 
 
 
   
  
 
 
 
 
    
  
 
 
 
 
 
  
  
  
 
 
 
 
  
   
  
 
  
 
 
   
 
  
 
 
 
 
  
 
 
  
 
   
 
 
 
   
  
 
 
 
   
   
 
  
 
  
 
 
 
 
 
 
 
 
 
   
  
 
 
  
 
  
  
  
 
 
  
 
 
  
 
 
  
 
  
 
  
 
 
  
 
 
 
  
  
 
  
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
  
    
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
   
 
 
  
 
 
   
 
 
 
   
 
 
     
 
 
 
 
 
 
 
 
  
 
 
 
 
    
 
 
 
 
   
 
  
 
 
 
 
 
   








 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
     
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
   
 
 
  
    
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
   
 
 
 
  
   
 
   
 
 
 
  
 
   
  
 
  
 
  
  
 
    
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
  
  
  
  
 
  
 
   
 
 
 
  
 
 
  
 
 
 
   
 
 
  
 
 
 
 
  
 
  
  
  
 
 
   
 
 
 
 
 
 
 
    
  
 
 
 
 
 
 
  
 
 
   
   
 
  
 
  
  
 
 
  
   
   
 
  
 
 
  
  
 
  
   
  
 
 
  
 
 
  
  
    
 
 
 
   
 
 
 
  
  
 
   
   
 
  
 
 
  
 
   
  
 
 
  
 
 
 
 
 
 
 
  
  
 
  
 
   
   
 
 
 
 
  
  
 
 
 
 
  
  
  
 
 
  
 
   
  
  
 
   
 
 
  
  
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
  
 
 
  
 
 
   
  
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
  
 
 
 
 
 
 
  
  
   
  
 
  
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
  
  
 
 
 
 
 
 
 
   
  
  
   
 
   
  
  
  
  
  
 
 
 
  
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
   
 
  
   
   
   
 
  
  
 
 
  
 
 
 
   
  
 
 
  
  
 
 
 
 
 
 
 
   
 
 
 
 
 
   
  
 
 
  
   
  
  
 
  
 
 
 
 
 
 
 
   
  
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
  
 
    
 
  
 
  
  
  
 
 
  
  
 
   
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
  
 
 
 
  
 
  
 
  
 
  
  
  
 
 
  
 
   
 
  
 
 
 
  
  
    
   
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
  
 
  
 
 
   
   
 
  
 
 
  
   
   
 
 
 
  
 
 
 
 
 
   
   
 
   
  
  
 
 
 
 
 
 
   
 
  
 
 
  
 
 
  
 
  
   
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
  
   
 
  
 
  
 
  
  
 
 
 
 
 
 
 
 
 
   
 
 
   
 
   
   
  
   
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
   
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
   
 
  
 
  
 
 
 
 
  
 
 
  
  
 
  
 
    
 
 
  
 
 
 
  
  
  
   
 
  
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
    
 
  
 
 
 
 
 
 
   
  
 
  
    
 
  
  
 
  
 
 
  
 
 
  
 
 
 
 
 
 
   
 
   
 
   
 
   
 
   
 
 
   
 
 
 
 
 
   
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
   
  
  
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
  
   
 
 
  
 
   
 
   
 
   
  
  
 
 
 
 
 
 
  
 
  
 
    
 
 
  
 
 
 
   
 
 
 
 
  
 
 
 
   
 
  
  
  
  
  
  
 
  
 
  
 
   
 
 
 
 
 
 
 
  
    
  
 
 
  
 
 
 
   
 
 
 
 
 
  
  
    
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
  
 
  
 
 
 
  
 
 
 
 
 
   
   
 
 
 
 
  
 
 
 
  
 
   
   
 
 
   
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
  
 
   
 
  
 
   
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
   
 
  
 
 
 
 
 
  
 
 
 
   
  
 
   
 
  
  
 
 
 
 
 
 
  
  
 
 
 
 
  
   
  
  
  
 
 
   
 
 
 
 
  
 
 
  
 
 
 
   
   
 
  
 
  
 
  
 
  
 
  
 
  
 
 
 
  
 
  
 
 
   
 
 
 
  
 
  
 
 
  
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
  
 
 
 
 
 
 
   
   
 
 
  
   
 
 
 
 
 
 
 
 
  
   
 
 
 
 
  
 
   
  
   
 
 
 
 
 
 
 
  
  
 
 
 
  
   
 
   
 
 
 
 
  
 
  
     
 
 
   
  
 
  
 
 
   
 
 
  
   
 
  
  
 
 
 
 
 
    
 
 
 
  
 
  
 
  
  
  
   
 
  
 
 
 
 
 
 
 
 
 
  
 
  
   
 
  
 
 
 
 
  
   
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
   
 
 
 
  
 
  
 
 
 
 
  
 
 
 
  
  
  
 
  
 
   
 
  
   
  
   
 
  
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
   
  
 
 
 
  
 
 
   
 
 
 
  
 
   
 
  
 
   
  
 
 
 
 
 
 
 
   
 
   
  
 
 
   


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
  
 
  
 
  
 
 
 
 
  
 
   
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
   
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
    
   
 
 
 
 
  
 
    
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
     
 
 
   
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
     
 
 
   
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
   
 
 
 
 
 
  
   
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
  
  
 
 
 
 
 
  
  
 
 
  
 
   
 
 
 
  
 
 
   
  
 
  
 
  
 
  
 
  
    
 
  
  
 
  
  
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
   
   
 
 
  
 
 
 
   
  
 
 
 
 
 
  
 
 
 
   
 
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
  
  
 
 
  
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
  
  
 
  
 
 
   
  
 
  
 
  
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
   
   
 
 
  
 
 
 
   
  
 
 
 
 
 
  
 
 
 
   
 
  
 
 
 
 
  
   
 
 
 
  
  
   
 
 
 
 
 
  
  
 
   
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
  
  
 
  
 
 
 
 
 
 
 
  
   
 
 
 
 
 
   
 
   
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
   
 
 
 
  
 
  
  
 
  
 
 
 
  
   
 
 
 
 
 
 
 
  
  
   
 
 
  
  
  
 
 
  
  
 
 
 
  
 
  
 
  
 
 
 
  
 
 
 
 
 
  
 
   
 
 
 
 
  
 
 
 
 
  
 
  
  
 
  
 
  
 
 
 
 
    
  
  
 
 
 
  
  
 
  
   
 
 
  
   
 
  
  
  
 
  
  
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
  
  
 
 
 
  
   
 
  
   
 
  
 
 
 
  
   
   
   
 
 
  
   
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
   
   
  
  
  
 
  
  
 
 
 
  
   
 
  
   
 
  
  
 
  
   
 
 
 
 
 
   
 
 
 
  
 
  
  
   
 
 
 
 
  
  
  
 
 
 
 
 
   
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
  
  
 
 
 
  
  
 
 
 
   
   
 
 
 
 
 
 
 
 
  
 
  
  
 
 
  
  
  
 
   
   
  
 
 
  
 
  
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
  
 
 
 
  
 
  
 
  
   
 
 
  
 
 
 
 
  
 
 
 
  
 
    
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
  
  
 
  
  
 
 
  
 
   
 
  
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
 
  
 
  
 
   
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
  
  
 
  
 
 
 
 
 
   
 
 
 
  
  
 
  
 
 
  
 
 
 
  
  
 
 
  
 
  
 
 
 
 
  
  
 
    
 
 
 
 
 
 
  
  
 
  
 
 
 
   
 
  
 
 
 
  
    
 
  
  
 
 
 
  
 
 
 
 
   
  
  
 
 
 
 
 
 
  
   
 
 
  
 
  
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
    
  
    
 
 
  
 
  
 
 
 
  
 
 
 
   
  
  
  
 
  
 
 
 
 
  
 
 
    
 
  
 
 
 
   
  
   
  
  
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
  
 
 
 
  
  
  
 
  
 
   
   
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
   
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
    
  
 
 
 
 
 
  
  
 
 
 
    
   


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
  
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
   
  
 
 
 
 
 
 
 
  
  
  
 
 
  
 
  
 
  
 
  
 
 
 
 
  
  
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
  
  
  
  
 
  
 
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
  
  
 
 
 
 
 
 
    
 
  
 
  
  
  
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
  
  
  
 
  
 
  
 
 
  
   
 
 
 
   
 
 
 
 
  
 
  
  
  
 
  
 
 
  
  
 
 
 
   
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
  
 
  
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
   
 
 
  
 
  
  
  
 
  
 
  
 
 
  
   
 
 
 
 
  
 
 
  
 
  
 
 
  
 
  
 
  
  
 
 
  
   
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
  
 
  
 
 
  
 
  
 
  
 
 
 
  
   
   
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
   
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
  
  
  
 
 
 
   
 
 
 
  
 
  
  
  
 
 
 
  
 
 
 
  
 
 
  
 
  
  
  
 
  
 
  
 
 
  
   
 
 
 
 
 
 
 
 
  
 
  
 
  
  
  
 
  
 
 
  
   
 
 
 
 
 
 
 
 
  
 
  
  
  
 
  
 
 
  
   
 
 
 
 
 
 
 
 
  
 
  
  
  
 
  
 
 
  
  
 
 
 
 
 
 
  
 
  
  
  
 
  
 
 
  
   
 
 
 
  
   
 
  
 
   
 
 
 
 
 
 
  
   
 
 
 
   
 
 
   
 
 
  
 
 
   
 
   
 
 
 
 
     
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
    
  
 
 
  
 
 
 
   
 
 
 
 
 
  
  
    
 
  
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
  
 
 
   
 
 
  
 
  
 
  
   
  
 
  
 
 
 
 
 
  
  
  
 
 
 
   
 
  
 
   
 
  
 
 
 
  
 
 
   
 
   
  
 
   
 
  
  
 
 
 
   
 
  
 
   
   
 
 
  
 
 
 
 
 
 
  
   
  
 
 
  
   
  
   
  
 
 
  
 
 
  
  
     
  
 
   
 
 
 
  
  
 
   
   
 
  
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
  
 
  
 
  
 
 
  
 
  
 
 
   
 
   
 
  
 
   
 
 
 
 
 
 
   
 
 
   
 
  
 
   
 
  
  
 
 
   
   
 
 
  
 
 
 
  
  
  
 
  
   
  
  
 
  
  
    
 
  
  
   
 
  
 
 
   
 
 
  
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
   
 
 
  
   
 
  
 
 
   
  
 
   
 
 
 
   
  
 
 
  
 
 
  
 
   
 
 
 
 
 
 
 
  
   
   
  
 
 
 
 
  
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
  
 
 
 
 
 
 
 
  
 
 
   
  
 
  
 
    
  
 
  
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
   
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
  
  
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
   
 
 
  
 
  
   
 
 
    
  
 
 
   
 
  
 
 
 
 
  
   
   
 
  
  
 
 
 
   
 
 
  
 
 
  
 
   
  
   
 
 
  
 
 
 
 
  
 
 
 
 
    
 
  
 
 
   
 
 
  
 
   
   
 
 
 
  
    
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
   
   
 
  
 
 
  
 
  
 
 
  
   
  
  
 
 
 
 
 
 
 
   
   
 
 
 
 
   
   
   
  
   
 
 
 
 
   
  
 
 
  
 
  
 
 
 
 
  
  
 
 
 
 
  
 
  
 
   
 
 
   
   
 
 
 
  
  
  
   
 
 
  
  
 
 
  
 
    
  
 
 
 
  
 
   
 
  
 
   
 
 
  
 
  
  
 
  
 
 
 
 
 
 
   
   
  
 
 
  
 
 
 
 
  
  
 
 
  
 
 
 
   
 
  
 
  
 
 
  
   
 
 
 
 
 
 
 
  
 
 
 
  
  
 
  
 
 
  
   
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
    
 
 
 
 
  
 
 
  
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
   
 
  
 
 
  
 
 
 
   
 
  
 
  
 
  
  
  
 
 
 
  
 
 
   
 
 
   
    
 
 
   
 
 
 
 
 
    
   
 
  
 
  
 
 
  
 
 
  
    
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
   
 
 
 
   
 
  
 
 
  
 
   
 
 
 
  
   
 
 
 
 
 
  
 
  
 
  
   
 
 
  
 
 
  
 
  
 
 
 
  
  
 
 
 
  
  
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
  
  
 
 
  
  
 
 
  
   
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
  
 
  
 
  
 
 
  
   
 
 
 
 
   
  
 
 
 
  
 
 
  
 
 
  
   


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
   
 
 
 
 
  
 
 
 
  
 
 
 
 
   
 
 
   
   
 
  
 
  
 
 
 
 
    
 
  
 
  
 
  
 
  
  
  
  
 
   
 
  
 
 
  
 
 
 
 
 
 
 
   
  
 
  
 
 
 
 
  
   
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
  
 
  
 
 
 
 
  
 
 
 
   
  
  
  
 
 
 
 
  
 
  
   
 
 
 
  
 
 
   
  
 
 
   
   
 
  
  
  
 
  
  
 
 
  
   
 
   
 
 
  
 
 
  
 
 
 
 
   
  
 
 
 
   
   
 
 
 
  
   
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
  
 
  
  
  
  
 
 
 
 
 
 
  
 
  
  
   
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
  
   
 
 
  
   
 
 
 
  
  
 
 
 
  
 
  
  
 
 
   
 
 
 
 
  
 
 
 
 
  
   
 
 
   
  
  
  
 
 
  
 
 
 
  
  
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
    
  
 
  
  
  
  
 
    
   
 
 
 
   
 
  
 
  
  
 
 
 
 
  
 
  
  
 
  
 
 
  
  
  
  
   
 
  
 
 
 
   
 
 
  
 
   
 
 
  
  
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
  
 
 
  
 
    
 
  
 
  
 
  
 
  
 
  
  
 
  
  
 
  
 
 
 
 
 
 
  
  
  
 
 
 
 
  
 
  
  
 
  
  
 
 
 
 
 
 
  
  
  
 
 
 
 
  
 
  
  
 
  
  
 
 
 
 
 
  
   
  
 
 
 
 
 
 
  
  
  
 
 
 
 
  
 
  
  
 
  
  
 
 
   
   
 
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
   
 
 
  
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
  
 
 
 
 
 
  
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
   
 
  
 
  
   
 
 
  
 
  
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
  
 
  
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
   
 
 
  
 
  
 
  
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
  
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
   
 
  
 
 
 
 
    
 
  
 
  
  
 
  
 
 
 
 
  
 
   
   
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
  
  
  
 
 
 
   
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
  
  
 
 
  
  
 
  
 
 
 
  
  
 
 
   
 
 
 
 
 
 
    
 
 
 
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
   
 
 
  
 
  
 
 
 
   
 
 
 
  
  
 
  
 
  
 
 
  
 
 
 
 
  
   
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
  
  
 
 
  
  
 
  
 
  
 
 
 
 
  
 
 
 
    
 
  
  
 
 
  
 
   
 
  
   
 
  
  
 
 
 
 
  
 
 
    
  
   
 
  
 
 
 
 
  
 
 
  
   
 
 
 
   
 
  
 
 
  
 
 
 
  
 
   
  
 
  
  
 
 
   
  
 
 
  
 
 
 
 
  
 
 
  
  
 
  
 
  
 
 
  
 
   
 
 
 
 
 
 
 
 
 
    
   
 
 
 
 
 
  
   
 
  
 
 
 
 
  
  
 
  
 
  
 
  
 
  
 
  
 
   
  
 
 
  
  
 
   
   
 
   
   
 
 
  
  
  
 
 
 
 
 
 
  
   
 
  
 
 
 
 
 
  
 
 
  
 
 
  
 
   
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
   
 
 
  
 
 
 
  
   
 
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
   
  
 
  
  
 
 
 
 
 
 
 
 
 
 
  
     
 
 
   
 
 
  
 
   
 
  
 
 
 
 
 
   
 
 
 
     
 
 
  
  
 
 
   
  
  
 
  
   
 
  
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
   
    
  
  
 
 
  
 
  
   
 
 
  
  
 
 
  
  
 
  
   
 
  
   
   
 
 
  
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
  
 
   
 
 
   
 
 
    
 
 
 
   
  
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
  
  
 
  
 
 
 
 
 
 
 
 
 
  
    
  
 
 
  
 
 
 
   
 
 
 
 
 
  
  
    
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
   
  
   
 
 
 
  
 
  
 
 
  
  
  
 
 
 
   
 
  
 
  
 
 
 
  
 
  
   
 
 
 
  
   
 
 
  
 
 
 
 
 
  
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
  
 
 
  
 
  
  
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
  
  
 
 
 
 
 
 
   
   
 
   
    
 
   
 
   
 
 
   
 
 
 
 
 
  
  
 
  
 
 
 
 
   
 
   
 
 
   
 
 
 
 
 
  
  
  
 
 
  
 
 
 
 
  
 
 
 
  
  
 
 
 
 
  
   
 
 
   
 
 
 
 
  
 
 
 
 
  
   
 
  
 
 
  
  
 
  
 
   
 
 
 
  
  
   
 
   
 
 
  
 
  
 
 
 
 
 
 
 
 
 
    
  
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
  
 
 
 
  
 
 
 
 
 
   
  
 
 
 
 
  
 
 
 
 
 
   
  
 
 
 
 
 
 
 
  
 
 
 
 
   
 
  
 
  
 
  
  
  
 
 
 
 
 
 
  
   
 
 
  
 
 
 
 
 
  
 
 
 
   
 
  
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
   
 
 
  
 
  
 
 
 
 
 
   
  
 
    
 
  
 
  
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
  
  
  
 
 
 
 
  
   
   
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
   
  
 
  
 
 
  
  
 
 
 
   
  
 
 
  
 
   
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
   
 
  
  
 
 
 
 
   
  
   
 
  
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
   
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
   
   
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
  
 
  
 
  
  
 
   
 
  
  
 
 
 
 
   
  
 
  
   
   
 
 
 
 
 
 
   
  
 
   
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
  
 
 
 
 
 
   
   
 
 
 
 
 
  
  
  
 
 
 
 
 
  
  
 
 
 
   
 
  
  
 
 
 
 
 
   
 
 
 
  
 
 
 
  
  
  
 
  
 
 
   
  
 
 
  
 
  
 
  
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
   
   
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
   
 
 
 
  
    
  
 
 
   


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
  
 
   
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
   
 
  
  
 
   
 
  
 
 
 
 
 
  
  
  
   
 
 
 
 
 
  
  
 
 
 
   
 
 
  
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
  
 
   
 
   
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
   
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
   
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
    
  
 
 
  
 
 
 
   
  
   
 
 
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
   
   
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
     
   
 
 
 
  
    
  
 
 
   


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
  
 
   
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
   
 
 
 
 
  
 
    
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
  
 
   
 
   
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
   
 
 
 
  
 
 
 
 
   
 
 
 
   
    
  
 
 
  
 
 
 
   
  
   
 
 
  
 
  
 
  
  
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
  
  
 
 
 
  
 
  
   
  
 
  
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
  
 
 
  
 
  
 
 
  
  
   
  
 
 
 
 
 
   
   
 
  
 
  
 
 
  
 
 
  
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
  
 
  
 
 
 
  
 
 
   
  
 
  
  
 
   
  
  
 
 
  
   
  
 
 
    
 
 
 
 
 
  
  
  
 
  
 
 
   
 
 
 
  
  
   
 
 
 
  
  
 
   
   
 
  
 
   
   
 
 
  
 
 
 
  
 
   
  
  
 
 
 
 
 
 
 
 
  
   
 
 
 
 
   
   
  
 
  
 
 
 
 
 
 
 
 
  
  
 
  
 
  
 
 
  
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
   
  
   
 
 
  
 
   
 
 
  
 
  
 
   
 
  
 
 
  
  
   
 
 
 
   
   
 
 
 
  
 
 
 
 
    
  
  
 
   
 
 
 
 
  
  
 
 
 
 
 
  
 
  
  
 
 
 
   
   
 
 
 
  
 
   
   
 
 
  
 
 
   
 
   
  
  
  
 
 
 
  
 
 
 
 
 
  
 
 
   
  
  
 
 
 
   
   
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
  
 
  
  
   
 
 
 
  
 
  
 
 
   
   
  
  
    
  
 
  
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
  
  
 
  
 
   
 
 
 
  
  
  
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
  
 
   
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
  
 
  
 
   
 
  
 
 
  
 
  
 
 
  
  
 
 
 
 
 
  
 
 
 
  
 
  
 
 
  
 
   
  
  
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
   
   
   
   
  
 
 
 
  
 
    
   
  
  
  
 
 
 
  
 
 
 
 
  
 
   
 
   
 
   
 
  
 
 
 
  
 
 
 
 
   
  
 
  
 
  
 
 
 
 
 
 
  
 
 
   
 
 
   
  
 
 
  
  
   
  
 
  
  
    
   
  
  
  
 
 
 
  
 
 
 
 
  
 
   
 
   
 
     
  
 
 
 
  
 
 
 
  
  
 
  
   
 
 
 
 
 
 
  
 
 
   
  
 
   
  
  
 
   
   
  
  
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
  
  
 
 
  
  
 
 
 
 
 
 
 
 
   
 
   
  
  
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
  
 
 
 
  
   
 
 
  
 
 
 
    
  
 
  
 
  
  
 
   
  
 
  
 
  
 
   
   
  
 
 
    
 
 
   
   
  
  
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
 
  
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
  
 
 
 
  
 
  
  
 
  
  
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
    
 
   
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
   
  
 
  
   
 
 
 
 
  
 
  
  
 
  
  
 
 
 
 
 
 
 
  
  
 
 
 
  
   
   
 
   
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
   
  
  
 
 
  
 
  
 
 
 
   
 
   
  
  
 
    
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
   
  
   
 
 
    
  
 
   
   
 
 
  
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
   
 
   
 
 
  
 
 
 
  
 
 
 
  
   
 
   
 
 
  
 
   
 
 
   
 
 
  
 
   
  
    
 
  
   
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
  
 
  
 
 
 
  
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
   
   
     
   
  
 
  
  
 
  
   
 
 
 
 
 
  
  
  
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
  
  
 
  
  
 
  
  
  
 
 
 
 
 
 
 
  
 
  
 
 
  
 
  
 
  
  
  
   
 
 
 
 
 
 
   
 
  
 
 
 
  
  
 
 
  
 
 
 
   
 
  
   
   
 
 
 
 
 
 
 
 
  
  
 
 
  
 
  
 
 
 
 
  
  
  
  
 
 
 
 
 
 
   
 
  
 
  
 
   
  
 
 
 
 
 
   
 
 
 
  
   
 
  
 
 
  
 
  
   
 
  
 
 
  
 
  
   
 
   
 
 
 
 
 
 
 
  
 
 
  
  
   
   
 
  
  
   
  
 
 
  
 
 
  
 
  
 
  
 
  
   
  
 
  
 
 
 
  
  
 
   
   
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
  
 
   
  
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
   
  
 
  
  
 
 
 
 
 
 
 
 
 
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
   
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
  
 
  
 
 
 
 
  
 
  
 
 
  
 
 
 
  
   
 
   
 
  
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
  
 
  
 
 
  
  
 
  
 
  
 
 
  
   
 
  
 
 
  
   
 
   
 
 
 
  
 
  
 
 
 
  
 
   
  
 
  
 
 
 
   
  
 
 
  
  
  
  
  
     
  
 
 
 
 
 
 
  
  
 
   
  
  
 
 
 
   
   
 
 
 
 
  
 
 
 
 
 
 
  
 
  
  
 
  
 
 
 
 
 
 
  
 
   
 
   
  
 
  
  
   
 
  
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
  
 
  
  
 
 
  
 
 
    
 
 
   
  
 
 
  
 
  
 
 
  
 
  
  
   
 
   
 
   
   
 
 
 
 
 
 
 
 
 
 
   
    
 
 
 
     
  
  
 
 
  
 
   
 
  
   
 
  
   
 
  
 
  
 
  
 
 
 
   
 
 
   
 
 
  
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
  
   
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
   
   
 
 
  
   
 
 
  
   
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
   
  
 
  
 
 
 
  
 
  
   
  
 
  
  
 
 
   
 
 
 
  
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
  
   
 
 
 
 
 
  
  
  
 
 
 
 
   
  
 
 
 
 
   
   
 
  
 
 
 
 
 
  
 
 
 
 
 
    
 
 
 
 
  
 
 
 
    
 
 
  
 
 
  
   
 
 
 
   
 
  
  
 
  
   
 
  
 
 
 
 
  
  
 
 
  
   
 
  
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
   
 
 
   
  
  
 
 
  
 
 
 
 
   
  
 
 
 
 
   
  
   
 
 
  
 
 
 
  
  
 
    
  
 
 
  
 
 
  
  
 
  
   
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
  
 
     
 
 
 
    
 
 
  
 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
   
  
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
     
   
 
  
  
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
     
 
   
  
 
 
 
 
 
 
 
   
 
  
 
 
 
  
 
 
  
 
 
 
 
 
   
  
 
   
  
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
   
  
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
   
  
 
   
 
  
 
 
 
  
  
  
 
 
 
   
 
 
 
 
 
 
 
  
 
   
 
  
 
 
  
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
  
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
  
 
  
 
 
 
  
  
 
 
 
 
  
 
 
  
   
 
   
   
 
 
 
 
 
 
  
  
 
 
  
 
   
  
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
   
 
 
  
 
 
 
 
  
 
   
  
 
  
 
 
   
 
 
  
 
   
 
 
  
 
 
 
  
  
 
 
  
  
 
  
 
 
  
 
 
 
   
 
 
    
  
 
 
 
 
 
 
 
   
   
 
 
  
 
 
   
  
  
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
  
 
  
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
   
  
 
 
 
  
 
  
 
  
 
   
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
  
   
   
  
 
   
  
 
 
 
 
 
 
 
  
 
   
 
  
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
    
 
 
   
 
  
 
  
  
  
 
 
    
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
  
   
 
 
  
 
  
 
 
  
 
 
 
   
 
 
  
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
 
 
 
   
 
 
 
 
 
  
   
  
 
  
 
 
  
  
 
 
  
 
 
   
  
 
  
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
   
 
 
 
 
 
 
  
  
 
 
 
 
 
  
  
 
  
 
  
  
 
  
 
 
 
 
  
   
  
   
 
 
  
  
  
 
 
 
 
 
  
 
 
  
 
 
  
 
   
 
 
   
  
  
 
  
 
 
 
  
 
 
  
   
  
 
 
 
 
 
 
    
 
 
 
  
 
  
  
  
  
  
 
 
 
 
 
 
  
   
 
 
  
  
  
 
 
 
  
   
  
   
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
  
  
 
  
 
    
 
  
 
   
     
  
 
 
  
 
  
   
 
 
 
   
 
 
 
 
 
   
  
 
 
  
  
   
 
 
 
  
 
 
  
 
   
 
 
  
  
 
 
  
  
  
 
 
 
 
 
 
 
 
  
 
 
  
 
  
  
  
 
 
  
 
  
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
   
   
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
  
 
  
  
  
 
 
   
 
 
  
 
 
 
  
 
 
  
 
  
 
  
 
   
   
 
 
  
 
   
  
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
  
 
  
 
  
 
  
  
  
 
  
  
 
  
 
 
   
 
 
 
  
 
  
 
 
 
  
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
  
 
 
 
  
  
 
  
 
 
 
  
  
 
 
  
 
  
 
  
   
 
    
 
   
 
  
 
 
 
  
   
 
 
 
   
  
 
 
 
  
    
 
 
 
  
 
 
 
   
   
 
 
  
 
  
 
  
 
 
 
  
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
    
  
 
 
   
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
  
  
  
 
 
 
   
  
  
 
 
 
 
 
 
  
  
 
 
 
    
   
 
 
 
 
 
  
  
 
 
 
 
 
 
    
 
  
 
 
 
 
 
  
 
 
 
  
 
     
 
   
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
  
  
 
 
  
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
   
 
  
 
 
 
 
 
    
 
 
 
  
  
 
 
  
 
  
 
 
 
 
 
 
   
   
  
 
  
  
 
 
 
 
 
 
 
  
 
 
 
  
  
 
   
   
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
   
  
 
  
 
 
  
  
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
  
  
 
  
 
  
  
 
 
    
   
 
 
 
  
  
 
  
  
 
 
  
 
 
  
 
 
 
  
 
 
 
  
  
   
 
  
  
   
 
 
  
  
  
  
 
  
  
  
 
 
    
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
  
 
 
 
   
 
   
 
 
 
  
  
 
 
  
  
 
  
  
  
 
 
 
  
 
  
   
   
 
 
 
   
 
 
 
 
 
 
 
  
 
 
  
 
 
   
 
  
 
 
 
 
 
  
  
   
  
  
 
 
 
   
  
  
 
 
 
  
 
  
 
 
 
   
 
  
 
   
  
  
 
  
  
 
  
 
   
 
 
   
 
  
 
  
   
  
  
  
 
  
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
   
  
  
 
 
   
 
 
 
 
  
  
  
 
 
 
 
  
 
  
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
   
   
 
 
 
  
  
 
  
 
   
  
 
  
   
  
  
 
 
 
  
 
 
 
 
 
  
 
 
   
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
  
 
 
 
 
 
 
 
  
 
  
  
   
  
 
 
 
 
 
 
  
 
 
   
 
 
  
  
  
  
   


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
  
  
  
 
  
 
  
  
 
 
 
 
  
 
 
  
 
  
 
  
 
 
    
 
  
   
  
 
  
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
   
  
 
 
 
  
 
 
 
 
 
  
 
  
   
   
  
 
  
 
   
 
  
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
   
   
 
  
 
  
   
 
 
  
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
   
  
  
  
 
 
 
 
 
 
  
  
  
  
 
 
 
  
  
 
 
  
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
   
  
 
 
 
 
 
 
 
 
 
   
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
  
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
  
 
 
  
 
 
   
   
   
 
  
  
 
 
 
 
 
 
 
   


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
   
 
 
   
 
   
 
   
 
   
 
   
  
 
 
 
 
 
 
   
 
   
 
   
   
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
  
 
 
   
 
   
 
 
   
 
  
 
 
 
   
 
 
 
 
   
 
  
 
 
 
  
 
 
 
  
 
 
  
 
   
 
 
 
 
 
  
 
  
 
 
 
 
  
 
   
 
  
   
  
 
 
 
 
   
  
  
 
 
 
 
  
 
   
  
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
  
  
   
 
 
 
 
 
 
 
   
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
   
  
 
   
 
 
 
 
  
  
 
 
 
 
  
  
 
  
 
 
 
  
   
 
 
   
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
  
  
 
 
 
 
 
 
  
  
   
 
  
 
 
  
 
  
 
 
 
  
   
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
 
  
  
 
 
 
 
  
 
 
  
  
 
 
  
 
 
 
 
  
  
 
  
  
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
  
  
    
  
 
 
    
  
 
 
 
 
 
  
    
    
 
 
 
  
 
   
 
 
 
   
 
 
   
    
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
   
 
  
 
 
 
 
 
  
  
 
 
   
  
 
 
 
 
 
 
  
    
  
    
 
 
  
 
  
   
 
  
 
 
 
 
 
  
  
 
 
   
  
 
 
 
 
 
 
    
 
 
  
 
  
   
 
  
 
 
 
 
 
  
  
 
 
   
  
 
 
 
 
 
  
 
 
  
 
  
 
 
 
  
   
 
 
 
  
  
 
 
 
   
 
 
   
 
 
   
 
 
  
 
 
 
 
   
 
 
 
  
 
      
 
  
 
 
 
 
 
 
   
 
 
 
 
  
  
   
 
 
  
 
 
 
 
  
   
 
 
 
  
  
 
 
 
  
 
  
 
 
 
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
 
  
  
  
  
    
  
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
   
 
 
 
 
  
  
 
 
 
 
  
  
 
  
 
 
  
 
  
 
   
  
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
  
 
 
 
  
  
   
  
 
  
  
  
  
 
  
  
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
 
  
 
  
  
 
 
 
 
 
 
  
  
  
  
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
   
 
   
 
 
  
 
 
 
   
  
  
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
   
 
  
 
 
  
 
  
 
 
 
   
 
 
 
  
 
 
  
 
   
 
 
 
  
   
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
   
 
 
   
 
   
 
 
 
 
 
  
   
 
  
   
 
  
   
 
 
  
  
 
 
 
   
 
 
 
 
  
   
 
 
 
 
   
 
  
 
 
 
 
 
 
  
  
  
   
  
 
  
 
  
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
  
  
 
 
  
 
  
 
   
   
 
  
  
 
  
 
 
  
 
 
 
 
 
  
   
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
   
 
  
 
  
 
 
  
 
 
   
 
   
 
  
 
 
 
  
 
 
   
 
 
 
 
  
  
 
 
 
  
 
   
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
   
  
 
 
 
 
  
 
  
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
   
 
 
 
  
   
   
   
 
 
  
 
  
 
 
   
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
   
   
   
 
 
  
 
  
 
 
   
 
 
 
  
 
  
 
  
 
  
 
 
  
 
 
  
 
 
 
 
 
  
 
  
  
 
 
  
 
  
 
  
  
 
 
 
 
 
 
 
   
 
   
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
  
 
   
   
 
 
  
 
 
 
  
 
 
 
  
   
 
   
 
  
 
 
 
 
  
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
  
  
   
 
 
 
 
   
  
 
 
 
  
 
 
  
 
 
 
 
 
 
   
 
 
  
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
  
 
  
 
 
   
 
 
 
   
  
  
 
   
   
 
 
 
   
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
 
  
  
  
 
 
 
 
 
 
   
 
 
 
 
 
  
 
  
 
  
 
 
 
  
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
   
 
  
 
  
 
  
 
  
  
 
 
 
  
 
 
 
 
  
 
 
  
 
    
 
 
 
   
 
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
   
 
 
  
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
   
  
 
 
 
  
    
  
 
  
 
 
   
 
   
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
   
  
 
  
 
 
 
 
  
 
  
 
 
 
  
   
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
  
   
  
 
 
 
 
  
 
 
 
 
 
 
 
  
  
   
 
 
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
   
  
 
 
 
 
  
  
 
 
 
  
 
  
 
  
   
   
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
  
 
 
  
 
   
  
 
 
 
   
 
 
 
   
  
 
 
  
 
  
  
 
 
 
 
 
 
   
 
  
 
  
 
 
 
 
 
   
 
  
 
 
 
 
  
 
   
  
  
 
 
  
  
   
 
 
  
 
 
  
   
 
  
   
 
 
  
 
 
 
  
 
 
   
   
 
   
  
 
 
 
 
 
 
 
 
   
 
 
 
  
   
 
 
 
   
 
 
  
 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
  
 
  
   
 
 
  
 
 
  
 
 
   
 
  
 
 
  
 
 
 
 
 
 
 
   
 
 
  
  
 
 
   
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
   
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
  
   
 
   
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
   
  
 
 
 
  
   
 
 
 
  
 
   
 
 
   
 
 
 
 
  
 
  
 
 
 
 
  
   
 
  
 
    
 
 
  
 
 
 
   
 
  
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
   
  
 
 
 
 
 
 
   
 
  
   
  
 
 
 
 
  
   
 
 
    
  
 
  
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
   
 
 
  
 
 
 
   
 
   
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
  
  
 
 
 
  
  
  
 
 
   
 
 
 
 
 
  
  
 
  
 
 
  
   
 
   
 
 
   
 
  
 
  
 
 
  
 
   
 
 
 
 
  
   
 
  
 
  
 
 
 
 
  
 
 
  
 
   
 
 
 
  
 
 
 
 
  
 
   
 
  
 
    
 
 
  
 
 
  
 
   
 
  
  
   
 
 
 
  
 
   
 
 
 
 
 
  
 
   
 
 
    
   
  
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
   
 
 
  
 
 
 
  
   
   
   
  
  
 
    
 
 
 
 
 
  
 
 
 
 
  
   
 
 
    
 
 
  
  
   
 
 
  
 
  
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
  
 
 
  
 
  
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
   
 
 
  
   
 
   
 
 
 
 
 
 
 
 
 
 
 
   
 
   
 
 
 
  
   
 
   
 
  
 
 
 
 
 
  
 
 
 
   
  
 
 
 
 
  
 
 
 
   
 
 
 
 
  
 
  
  
 
 
 
 
 
   
 
  
 
   
 
  
  
 
  
  
 
 
  
  
 
  
 
 
 
  
   
 
 
  
 
 
 
   
   
  
 
 
 
 
 
   
 
 
 
 
  
 
 
 
  
   
 
 
 
  
 
 
 
    
   
  
 
 
 
 
  
   
 
 
 
 
  
 
 
  
 
  
  
  
 
 
 
 
  
  
 
    
 
 
  
   
 
 
  
 
  
 
 
  
   
 
   
  
 
 
 
   
 
  
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
  
 
 
  
 
   
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
   
 
 
 
 
 
   
 
   
 
   
 
 
 
 
  
 
 
 
   
  
 
 
 
 
  
 
 
 
   
 
   
  
 
 
 
 
 
   
 
  
 
   
 
  
  
 
 
  
 
 
 
 
  
  
 
  
 
 
 
 
  
   
 
 
  
 
 
 
 
   
   
  
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
  
 
   
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
   
 
  
 
   
  
 
 
  
 
 
    
  
 
   
  
  
 
  
  
    
  
 
 
  
  
 
  
 
 
 
   
 
  
  
   
 
 
 
  
    
  
 
 
 
 
   
 
 
 
  
    
  
 
 
 
 
 
 
 
 
    
 
  
  
 
 
 
  
   
 
 
 
 
 
 
 
   
 
 
  
 
  
 
 
  
 
 
   
 
 
   
 
  
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
  
   
 
 
 
 
 
   
 
 
 
  
 
 
 
  
  
 
 
  
  
 
   
 
  
 
  
 
 
  
   
 
 
  
   
 
 
   
 
 
  
 
 
 
 
 
  
  
 
 
 
 
  
 
   
   
 
 
 
 
  
 
 
   
 
  
 
 
 
 
  
 
  
  
 
   
 
   
 
 
  
 
  
 
 
 
 
 
 
    
  
  
 
 
  
   
  
 
 
 
  
   
 
 
    
  
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
  
  
  
  
 
 
 
  
   
 
 
   
 
 
 
  
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
  
 
  
   
 
  
 
  
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
   
 
  
   
 
 
  
  
 
 
 
   
 
 
   
  
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
  
  
 
 
  
  
 
  
  
  
 
  
   
 
  
   
  
 
 
  
  
  
  
  
 
 
 
 
 
  
 
  
 
  
 
 
 
   
 
 
   
  
  
 
  
 
 
  
 
 
 
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
  
 
 
   
 
 
 
  
  
 
 
  
 
 
  
 
   
 
 
 
  
 
   
 
 
 
   
 
 
 
    
 
 
 
 
 
 
 
 
 
   
  
 
 
  
 
 
 
 
 
 
   
 
 
   
 
 
 
 
  
  
 
 
 
 
 
 
 
   
   
 
 
  
  
  
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
   
  
 
   
   
 
 
  
 
 
   
  
 
  
 
   
  
 
   
 
   
 
   
 
 
 
  
  
 
  
 
 
  
   
 
 
    
 
 
 
 
 
  
 
  
   
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
    
 
 
 
   
 
 
 
    
 
 
 
  
  
 
 
 
   
 
 
  
 
 
 
   
 
 
 
  
 
  
   
 
 
 
 
 
    
  
   
 
 
 






 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
   
  
 
  
  
 
 
 
  
  
  
 
  
 
  
 
   
 
 
 
 
 
 
  
 
 
   
   
 
 
  
 
 
 
 
 
   
 
  
   
 
 
 
 
 
   
  
 
 
  
 
  
 
 
  
   
 
 
  
 
 
 
 
 
 
 
  
 
  
   
 
  
 
   
  
   
 
 
 
 
   
  
 
 
 
 
 
  
 
  
   
  
   
 
  
  
   
 
 
   
 
  
   
 
 
   
  
  
  
 
 
 
 
 
 
 
 
   
 
 
   
 
 
   
 
  
 
  
 
 
 
   
 
  
 
 
  
 
  
  
 
 
 
 
  
  
 
 
 
  
 
  
 
   
 
 
 
 
 
 
  
 
 
   
   
 
 
  
 
  
 
 
   
 
  
   
 
 
  
 
   
  
 
 
   
 
  
 
  
  
 
 
 
   
 
 
  
 
   
   
 
 
  
 
  
 
 
  
  
  
  
 
 
  
 
 
  
  
   
  
  
 
 
 
  
  
  
 
 
 
 
 
 
 
 
   
 
 
   
 
 
   
 
  
   
 
   
 
 
 
 
   
   
 
  
 
   
  
  
 
  
 
  
 
 
 
 
 
 
 
 
  
   
 
 
 
  
 
 
   
 
 
   
 
 
 
 
   
 
 
  
 
  
 
 
   
 
 
 
   


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
   
 
 
  
 
   
 
   
 
 
  
 
 
  
 
  
 
 
 
   
 
 
 
 
   
 
 
  
 
  
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
  
  
  
   
  
  
  
   
 
 
  
 
 
  
  
  
 
 
 
   
  
 
  
 
 
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
   
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
   
 
 
   
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
  
 
 
 
 
 
 
  
   
 
 
 
 
 
 
   
  
   
  
 
 
 
  
 
 
  
 
 
   
 
 
  
  
 
 
   
  
 
 
 
 
 
  
 
   
 
  
   
 
 
  
 
 
 
 
 
 
  
 
 
 
 
   
  
 
 
  
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
  
  
  
 
 
  
 
 
 
 
 
 
 
 
  
  
  
 
 
  
 
 
 
   
 
  
 
 
 
   
 
 
 
 
 
 
  
   
 
  
 
 
 
 
  
   
  
 
 
 
  
  
   
 
  
 
 
  
 
 
 
   
 
 
 
  
 
 
 
    
   
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
   
 
  
 
  
 
  
  
  
   
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
  
 
  
    
  
 
 
 
 
    
  
  
 
 
 
 
 
 
   
 
 
 
 
   
  
 
 
 
  
 
 
 
 
 
  
 
 
   
 
  
 
 
 
  
 
 
  
 
 
 
  
  
 
  
    
 
  
  
 
 
   
 
 
  
 
 
  
   
 
 
   
  
 
 
 
 
 
  
 
  
 
 
 
 
  
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
  
  
  
 
  
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
  
   
   
 
 
 
 
 
  
 
 
 
  
 
 
   
 
   
 
  
 
  
 
  
  
  
 
 
 
 
  
  
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
   
 
  
 
 
 
  
 
 
   
   
 
   
  
 
 
  
 
 
 
 
 
 
 
  
   
  
 
 
 
 
  
 
 
  
 
 
 
 
  
   
 
   
 
 
 
  
  
  
 
  
 
   
 
 
 
 
 
 
  
  
   
 
  
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
  
 
  
 
   
 
 
 
 
  
  
  
   
 
  
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
   
 
  
  
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
  
   
  
  
 
 
   
 
 
  
 
 
 
 
  
 
 
 
  
 
 
   
  
 
  
 
   
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
   
  
 
 
 
 
   
 
 
 
 
  
 
 
 
   
 
 
 
 
  
  
  
 
 
 
 
 
 
 
   


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
   
   
 
 
 
 
   
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
  
   
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
  
 
 
  
 
 
  
   
 
  
 
 
 
 
 
   
 
 
 
  
 
 
  
 
 
  
  
 
   
 
   
 
 
  
  
 
 
 
 
 
  
 
 
   
  
 
 
 
 
  
   
  
 
 
  
 
 
  
  
    
  
 
   
 
 
 
  
   
   
 
  
 
 
 
 
 
 
 
 
 
 
  
 
   
  
  
 
 
 
   
   
 
 
  
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
   
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
    
   
 
 
 
 
  
 
    
  
 
 
 
   
  
 
   
 
  
 
 
 
 
  
 
 
  
 
  
   
 
 
 
  
   
 
  
  
 
  
  
   
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
 
   
  
 
 
 
   
   
  
  
 
   
  
 
  
   
  
 
 
  
  
 
   
 
 
   
  
 
  
  
 
   
  
 
  
  
 
   
 
 
   
 
   
  
 
   
 
 
   
   
 
  
  
 
 
 
   
 
  
 
 
 
 
   
   
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
  
  
 
  
 
 
 
  
 
 
 
 
 
  
  
 
 
   
  
 
 
 
 
  
  
 
  
  
 
 
   
   
 
 
 
  
  
 
 
  
   
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
  
 
 
  
  
 
 
 
   
   
 
  
 
   
  
 
  
  
 
  
 
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
  
 
 
   
  
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
  
 
  
 
 
 
  
 
  
  
 
 
 
 
 
  
 
  
 
  
 
 
 
  
 
   
 
  
 
   
   
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
  
 
 
 
   
  
 
  
 
 
 
 
 
 
   
 
 
 
  
 
 
 
  
  
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
  
  
 
 
  
 
 
 
 
 
  
  
 
 
 
  
 
  
 
 
  
  
 
  
  
 
 
   
    
 
 
  
  
 
  
  
 
 
   
   
 
 
 
  
  
 
 
 
  
 
 
 
  
 
 
   
 
 
  
  
 
  
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
   
 
 
 
 
   
   
 
 
  
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
  
   
 
 
 
  
 
 
   
   
   
 
 
 
 
   
   
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
   
 
 
 
  
 
   
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
   
  
 
   
 
 
  
  
 
 
 
 
  
   
 
   
  
 
  
 
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
   
 
 
   
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
  
 
 
 
  
  
   
 
 
  
 
 
 
 
 
 
  
    
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
  
 
 
    
 
  
  
 
 
 
 
 
  
  
 
   
 
  
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
  
 
  
  
   
  
  
 
 
 
 
 
 
 
  
  
   
  
 
 
 
 
  
  
 
 
 
 
 
   
   
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
   
 
  
  
 
  
  
  
 
 
 
 
 
 
 
 
   
  
 
  
 
  
  
  
 
 
   
 
 
 
  
   
 
 
 
 
  
  
   
 
  
  
 
  
 
  
 
  
   
 
 
 
  
    
 
 
 
 
  
 
 
  
 
 
 
  
   
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
   
  
 
 
 
 
 
 
 
 
 
  
   
  
 
 
 
 
 
 
  
 
 
 
    
  
 
 
 
 
  
  
 
 
 
   
  
 
 
 
 
  
  
  
 
 
  
   
 
 
 
   
  
  
 
 
 
 
 
 
  
 
  
 
 
  
 
 
   
  
  
 
 
  
 
   
   
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
   
   
 
 
 
   
 
 
  
 
 
 
 
  
  
 
 
 
  
  
 
  
  
 
 
  
 
  
 
  
 
  
 
 
   
 
 
  
  
 
 
 
 
 
 
  
  
 
  
 
 
   
  
  
 
  
   
 
 
 
 
 
 
 
 
 
   
   
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
  
 
 
 
  
 
 
 
  
  
 
 
 
 
   
 
 
 
  
 
 
   
   
 
 
 
 
 
 
 
 
  
  
 
  
  
  
  
 
 
 
 
  
  
 
 
 
  
 
 
 
  
 
  
 
 
 
 
  
   
  
 
 
  
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
   
  
  
  
 
  
  
 
  
 
 
  
 
 
  
 
 
  
 
  
 
 
  
 
 
   
   
 
 
 
 
   
  
 
  
 
 
   
   
   
 
  
 
  
 
  
  
 
 
 
 
  
 
 
 
 
   
   
   
 
  
  
 
 
   
   
 
  
 
 
  
 
 
  
 
 
   
   
   
 
 
  
  
 
 
  
  
 
  
 
  
  
 
  
 
 
 
 
   
   
   
  
 
   
   
 
  
  
 
   
  
 
 
  
  
  
 
 
 
 
  
 
   
  
  
 
  
  
 
   
 
 
 
 
 
  
 
  
 
  
  
  
 
 
  
   
 
    
 
 
  
 
  
 
   
 
   
  
  
 
 
  
 
  
   
 
 
 
 
   
   
   
  
   
   
 
  
  
 
  
  
   
 
 
  
 
  
 
 
    
 
  
 
  
 
 
 
 
  
  
  
  
 
  
 
  
  
  
 
  
   
 
   
 
 
 
 
  
  
  
   
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
   
 
  
 
 
 
 
   
  
 
 
   
  
 
 
  
  
   
  
 
 
  
 
    
  
 
  
  
 
 
 
  
 
  
  
 
   
 
   


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
  
 
   
 
  
 
  
 
 
 
  
 
 
 
 
 
  
 
  
 
   
  
 
 
   
 
   
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
   
   
 
 
 
  
 
  
 
   
  
 
   
 
 
  
 
  
 
 
 
 
   
 
     
 
 
   
  
 
  
  
  
   
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
  
  
 
 
 
 
   
 
  
 
 
 
 
 
 
  
 
 
 
 
 
   
 
  
 
  
 
 
 
  
 
  
 
   
  
 
   
 
 
  
 
  
 
 
 
 
 
 
 
  
    
 
 
   
 
 
  
 
 
 
 
 
 
   
  
 
 
  
   
 
   
  
  
  
 
 
 
  
 
 
 
  
  
 
 
 
  
 
  
 
 
 
 
 
   
   
 
  
   
  
  
 
 
     
   
 
   
 
 
 
  
 
  
 
  
  
   
 
  
 
 
 
 
 
 
  
 
 
  
 
 
  
 
   
 
 
 
 
   
 
 
   
 
 
 
  
  
  
 
 
 
 
 
 
 
  
 
  
 
  
 
 
   
  
 
  
 
   
 
 
 
 
  
 
  
 
  
 
  
  
   
 
  
   
  
  
  
   
 
   
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
  
 
 
  
  
  
 
 
  
 
 
   
 
  
 
    
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
  
  
 
 
    
   
 
   
 
 
  
 
 
 
 
   
 
 
  
 
  
 
  
 
   
 
 
 
 
 
 
 
  
  
  
 
 
  
 
 
  
 
   
  
 
 
  
  
 
  
  
 
  
 
 
 
 
 
 
  
 
 
 
 
  
   
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
  
 
   
 
 
 
  
 
 
 
 
 
  
 
 
  
 
   
 
 
 
 
 
 
   
 
 
 
   
 
  
  
 
 
  
 
 
 
 
  
 
  
   
   
 
   
 
  
 
 
   
 
 
  
 
 
 
 
   
  
 
 
  
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
   
 
   
  
 
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
   
    
  
 
  
 
  
 
 
 
  
  
 
 
  
  
 
  
 
  
 
   
 
 
  
  
  
 
   
  
 
 
  
   
 
  
 
 
  
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
   
   
 
  
  
  
 
 
   
   
  
   
 
 
   
  
  
  
 
 
  
 
   
  
 
  
 
  
   
 
 
 
 
 
 
  
 
 
  
 
  
 
   
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
  
   
  
 
   
    
   
 
   
 
  
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
  
 
 
 
 
 
  
   
  
 
 
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
  
 
  
 
  
  
 
  
 
 
 
 
 
 
 
 
 
  
   
 
 
  
  
  
 
 
 
 
 
  
 
  
 
   
 
 
   
  
  
 
  
  
 
  
 
 
  
   
  
 
 
 
 
 
  
 
 
   
   
 
 
 
 
    
   
  
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
   
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
   
 
 
  
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
  
   
 
 
   
 
    
 
 
 
  
 
 
 
 
 
 
 
 
 
   
   
 
  
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
   
 
 
  
 
 
 
 
  
   
   
 
 
 
   
 
 
 
 
 
 
  
 
 
     
  
 
  
  
  
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
  
  
    
 
  
 
 
  
 
  
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
   
   
 
 
 
 
 
  
   
   
 
 
 
 
 
   
 
  
  
  
 
 
 
 
 
 
  
   
  
 
 
  
  
 
 
   
  
 
   
 
  
 
  
 
  
 
 
 
 
   
  
  
 
 
 
 
  
  
 
 
 
 
 
 
 
   
  
  
 
   
 
 
 
 
 
  
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
   
 
 
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
   
 
 
   
 
 
 
  
 
 
 
 
   
  
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
  
   
 
 
  
 
  
 
 
  
 
 
 
   
 
 
  
  
 
 
 
  
   
 
 
  
 
 
 
 
   
 
  
 
 
  
 
 
 
   
 
 
 
 
 
 
  
   
  
 
  
 
 
  
  
 
 
  
 
 
  
 
  
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
  
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
  
 
   
 
 
  
  
  
 
  
 
 
  
   
 
   
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
   
 
 
   
   
 
 
 
 
 
 
 
  
 
 
 
   
   
   
  
  
 
 
 
 
  
 
 
  
 
   
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
   
 
   
  
 
 
 
 
 
 
 
 
 
 
 
   
   
   
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
  
   
 
   
  
 
   
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
   
  
 
 
   
  
   
 
  
   
 
 
 
 
  
   
  
 
   
   
  
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
   
 
   
  
 
 
 
 
 
  
 
  
  
  
 
  
 
 
 
 
 
 
 
   
 
  
 
 
  
   
 
 
   
 
 
  
 
 
  
 
 
   
   
  
  
  
 
 
   
  
 
 
   
 
  
 
    
 
   
  
 
  
  
  
 
   
 
 
   
 
 
  
  
 
 
   
 
 
 
 
 
  
 
 
  
  
  
 
    
 
  
 
  
  
  
 
 
 
 
 
  
  
 
  
 
  
  
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
   
   
 
  
 
 
 
  
  
 
 
 
 
 
  
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
  
  
  
 
  
  
 
 
 
  
 
 
  
 
 
 
 
 
    
   
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
  
 
 
   
 
 
   
 
  
 
   
  
 
 
   
  
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
  
  
 
  
 
 
 
  
 
   
   
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
   
   
  
 
  
 
   
 
  
 
  
  
 
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
  
 
  
  
 
  
  
 
 
 
  
 
 
 
 
  
 
  
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
    
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
     
   
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
  
  
 
   
 
  
 
 
 
 
 
 
   
 
 
 
  
 
  
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
   
  
  
  
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
  
  
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
   
 
  
 
 
  
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
   
   
 
 
 
 
 
  
 
 
 
  
   
 
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
  
 
 
 
  
 
 
 
  
 
   
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
  
   
 
 
 
 
 
  
  
    
 
 
 
   
 
 
  
 
 
 
 
 
 
 
  
  
    
 
  
 
 
  
 
 
 
 
 
 
 
 
  
  
 
   
 
  
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
    
 
   
 
      
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
    
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
   
   
 
   
 
  
 
 
 
 
 
 
 
 
 
   
 
 
   
  
 
 
 
 
  
 
  
 
 
 
 
 
 
    
  
 
 
 
 
 
 
 
 
 
 
  
 
   
 
  
  
 
 
 
  
 
 
 
 
  
   
  
  
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
   
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
  
 
 
 
   
 
 
 
  
  
 
 
  
  
    
 
   
   
  
 
 
 
  
 
  
  
    
 
  
 
 
 
 
  
 
 
  
 
  
  
    
 
 
  
 
  
 
 
 
 
 
 
  
  
    
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
    
 
 
 
  
 
 
  
  
  
 
   
 
   
 
  
  
  
 
 
 
 
  
 
    
 
  
 
 
 
 
  
  
 
 
  
  
    
  
 
 
 
  
 
 
 
 
 
 
 
 
  
    
 
  
   
 
 
 
 
  
 
 
 
 
  
  
     
  
 
  
 
 
 
 
 
  
 
  
 
 
    
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
    
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
   
 
   
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
 
 
  
    
 
  
  
 
 
 
 
 
 
 
 
  
 
  
  
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
   
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
  
 
  
 
 
  
 
 
  
  
 
 
 
  
  
 
   
 
 
 
   
 
 
 
 
 
 
 
  
  
 
  
 
  
 
 
 
 
 
 
 
 
     
 
  
  
 
 
 
 
 
  
 
  
  
    
 
 
  
  
 
  
  
 
  
 
 
 
 
 
 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
   
 
 
 
 
 
  
 
 
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
  
 
 
 
  
 
  
 
 
 
 
 
  
  
  
 
 
 
 
  
  
 
 
 
 
 
 
    
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
  
  
      
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
  
  
  
  
    
  
  
  
 
 
  
  
  
  
 
 
 
  
  
 
 
 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
    
  
  
  
  
    
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
    
  
  
  
  
    
  
  
  
  
  
  
  
  
  
 
  
  
 
  
  
    
  
  
  
  
    
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
    
  
  
  
  
    
  
  
  
  
  
  
  
  
  
 
  
  
 
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
    
  
  
  
  
    
  
  
  
  
  
  
  
  
  
 
 
 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
 
 
  
  
  
  
  
    
  
  
  
  
    
  
  
  
  
  
  
  
  
  
 
 
 
 
 
  
 
 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
      
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 


 
 
 
  
 
 
     
 
 
  
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
  
  
  
 
 
 
 
  
  
 
 
 
 
 
 
    
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
  
  
      
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
  
  
  
    
  
  
  
  
    
  
  
  
  
  
  
  
  
  
 
 
 
  
  
  
  
      
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
 
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
  
  
  
      
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
 
 
 
 
 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
 
  
  
 
  
  
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
  
      
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
   
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
  
 
  
  
  
      
    
  
    
  
    
  
  
  
  
  
  
 
 
  
 
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 


 
 
 
  
 
 
     
 
 
  
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
  
  
  
 
 
 
 
  
  
 
 
 
 
 
 
    
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
  
  
      
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
  
      
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
      
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
   
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
    
   
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
  
 
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
  
 
  
  
  
    
  
    
  
  
  
  
    
  
  
  
  
  
  
 
  
  
  
  
  
    
  
  
  
  
    
  
  
  
  
  
  
  
  
  
 
 
 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
    
  
  
  
  
  
    
    
  
    
  
    
  
  
  
  
  
  
 
  
 
 
 
 
 
   
 
 
  
  
  
  
    
  
    
  
    
  
    
  
  
  
  
  
  
 
 
 
 
 
 
 
 
  
  
  
  
    
  
    
  
    
  
    
  
  
  
  
  
  
 


 
 
 
  
 
 
     
 
 
  
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
  
  
  
 
 
 
 
  
  
 
 
 
 
 
 
    
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
  
  
      
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
  
  
    
  
    
  
    
  
  
  
  
  
  
 
 
  
  
 
  
 
 
 
 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
 
 
 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
 
 
 
  
 
 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
 
 
 
 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
 
 
 
  
  
  
  
  
                
  
  
  
  
  
  
  
  
 
 
  
 
 
   
 
  
  
  
      
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
      
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 


 
 
 
  
 
 
     
 
 
  
  
 
 
 
 
 
 
  
  
 
 
 
  
 
 
  
 
  
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
  
 
  
 
 
  
 
  
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
  
  
  
 
 
 
  
 
 
  
 
  
 
  
 
 
 
  
 
 
  
  
 
  
 
 
  
 
  
 
 
 
  
 
  
 
   
 
 
 
  
 
  
 
 
  
 
 
 
   
 
  
 
  
 
  
 
 
 
 
 
  
  
 
 
  
 
 
  
 
 
   
 
 
 
 
 
  
   
 
 
 
 
 
  
  
  
 
 
 
  
  
 
 
 
 
 
 
  
  
   
 
   
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
  
   
  
 
 
 
  
 
  
  
 
   
 
  
 
 
  
   
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
  
    
  
   
   
 
  
   
  
  
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
  
   
   
  
 
 
 
 
 
  
  
 
 
 
 
   
 
  
 
 
 
  
 
 
   
  
 
 
 
 
 
 
   
  
 
  
    
 
  
 
 
   
   
  
 
   
  
   
 
 
   
  
 
 
 
    
   
   
 
  
   
  
 
 
 
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
    
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
  
    
 
 
 
 
 
 
   
 
 
 
  
 
 
 
   
 
 
  
 


 
 
 
  
 
 
     
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
  
 
   
 
  
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
   
 
 
 
  
 
 
 
  
  
    
 
 
 
 
 
 
   
 
 
 
  
 
 
 
   
 
 
 
   
 
   
  
    
 
  
 
   
   
   
 
  
 
  
 
 
 
 
 
   
    
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
  
  
 
 
  
 
 
  
   
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
    
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
   
 
 
 
    
 
 
 
 
 
  
  
   
 
 
   
  
 
   
 
  
  
 
 
 
 
   
  
 
  
 
  
   
  
 
 
  
   
 
 
  
 
  
 
 
  
 
   
  
 
  
 
 
 
  
 
 
  
    
  
     
  
 
 
 
 
   
  
 
  
 
 
  
 
  
 
 
   
  
   
 
 
 
  
 
  
 
 
  
  
  
 
 
 
   
 
  
 
 
 
 
 
  
 
  
 
  
  
 
 
  
  
 
  
   
 
  
   
 
 
  
  
 
 
  
  
 
  
  
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
  
 
 
   
  
 
  
  
 
  
  
  
 
 
 
 
 
 
 
  
 
  
 
 
  
 
  
 
  
  
  
   
  
 
 
   
 
  
 
 
 
  
  
 
 
  
 
 
 
 
  
  
 
  
  
 
 
  
  
 
 
   
  
 
 
    
 
 
  
  
  
   
 
 
 


 
 
 
  
 
 
     
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
   
 
 
 
  
  
 
 
  
   
  
  
   
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
   
 
 
  
 
 
  
 
 
 
  
 
  
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
   
  
 
 
 
   
 
  
 
 
   
 
  
 
 
 
 
 
 
 
 
  
 
  
  
 
  
 
  
 
 
 
   
  
   
  
 
  
 
 
 
   
  
 
 
 
  
 
  
  
 
     
 
 
 
  
  
 
     
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
  
 
 
 
 
   
 
 
 
 
  
  
 
 
  
 
  
   
   
 
   
 
   
   
 
 
  
  
   
  
  
 
   
 
   
   
   
 
  
 
  
  
  
 
 
 
 
 
 
 
  
  
 
   
 
 
  
 
 
  
 
    
   
 
  
 
  
 
  
  
  
 
 
 
  
   
  
   
  
 
  
 
 
 
 
  
 
 
 
  
  
 
 
 
 
  
 
  
 
   
 
 
   
   
 
 
 
  
  
  
   
 
 
  
 
   
   
   
 
  
  
 
  
 
   
 
  
  
 
  
 
 
 
 
   
 
 
 
 
    
 
  
 
 
   
 
 
  
 
   
   
 
 
 
 
 
 
 
   
 
  
 
  
 
  
 
 
  
   
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
  
 
  
 
  
 
 
  
   
 
 
 
 


 
 
 
  
 
 
     
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
   
 
 
  
  
 
  
 
 
  
 
 
 
 
 
  
 
   
 
  
 
  
 
  
 
  
  
 
 
 
  
  
 
 
 
  
 
 
  
 
 
   
 
 
 
 
  
 
  
 
  
 
  
 
 
  
 
  
   
 
 
  
 
 
 
 
  
   
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
  
  
  
  
   
  
  
  
   
 
 
  
 
 
  
  
  
 
 
 
   
  
 
  
 
 
  
 
 
  
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
   
  
 
 
  
 
 
  
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
  
  
 
  
 
 
  
 
  
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
  
 
  
 
 
 
 
 
  
  
 
  
 
  
 
  
  
   
 
 
  
 
 
 
   
    
  
  
 
 
 
   
  
 
 
  
 
 
 
  
  
 
  
 
 
    
   
  
  
  


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
   
  
 
 
 
   
 
   
 
 
 
 
 
 
 
 
 
   
 
   
  
 
  
  
  
 
 
  
 
 
  
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
  
 
  
 
 
  
  
 
  
   
 
 
 
   
 
   
   
 
  
 
 
 
 
 
 
 
   
 
 


















 
 
 
  
 
 
     
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
    
 
 
 
   
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
     
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
    
 
 
 
 
 
  
 
 
 
   
  
 
 
 
 
   
 
 
   
 
 
 
   
 
 
 
 
   
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
  
   
  
 
 
 
 
 
 
   
 
 
   
 
 
    
 
 
 
   
 
 
 
  
  
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 














 
 
 
  
 
 
     
 
 
 
 
 
  
  
 
 
 
 
 










 
 
 
  
 
 
     
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
 
  
 
 
 
 
 
  
  
  
 
 
  
  
    
 
 
 
   
  
   
  
 
   
 
  
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                              
                                                                                              
                                                                                              
                                                                                              
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
      
 
  
 
 
  
 
  
       
 
  
 
 
   
  
       
 
  
 
 
  
      
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
 
 
  
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
  
 
 
  
 
 






 
 
 
  
 
 
     
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
   
 
   
 
 
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
   
 
 
 
 
 
  
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
  
 


 
 
 
  
 
 
     
 
 
 
 
 
 
 
  
    
  
 
 
 
 
 
 
  
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
   
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
    
   
 
 
 
 
  
 
    
 
 
 
 
  
  
 
 
 
  
  
 
  
 
 
 

SAP_001.pdf: 
Official Title: A Phase IIB, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Dose-
Ranging Study to Assess the Efficacy and Safety of MSTT1041A in Patients with Uncontrolled 
Severe Asthma 
NCT Number: NCT02918019 
Document Date: SAP Version 2: 5 April 2019 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
CONFIDENTIAL
This is a Genentech, Inc. document that contains confidential information.  Nothing herein is to be 
disclosed without written consent from Genentech, Inc.
MSTT1041A—Genentech, Inc.
Statistical Analysis Plan GB39242
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE IIB, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER, 
DOSE-RANGING STUDY TO ASSESS THE EFFICACY AND 
SAFETY OF MSTT1041A IN PATIENTS WITH 
UNCONTROLLED SEVERE ASTHMA
PROTOCOL NUMBER:
GB39242
STUDY DRUG:
MSTT1041A (RO7187807)
VERSION NUMBER:
2
IND NUMBER:
129714
EUDRACT NUMBER:
2016-001549-13
SPONSOR:
Genentech, Inc.
PLAN PREPARED BY:
DATE FINAL:
Version 1: 20 May 2017
DATE AMENDED
Version 2: See electronic date stamp below
Name
Reason for Signing
Date and Time
(UTC)
05-Apr-2019 08:05:56
Company Signatory


MSTT1041A—Genentech, Inc.
2/Statistical Analysis Plan GB39242
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
The Statistical Analysis Plan (SAP) has been amended primarily to align with recently 
amended Protocol version 4.  Major changes, along with a rationale for each change, 
are summarized below:

The initial timepoint for measurement of efficacy endpoints has been specified as
baseline.  This is to accommodate the different baseline definitions in efficacy 
endpoints deemed appropriate and clinically relevant.  The definition of baseline for 
each endpoint is the randomization visit (Week 2) unless otherwise specified in 
Section 4.

The exploratory efficacy endpoint of change in nighttime symptoms has been 
removed, as this endpoint was included in error in the previous protocol version. 
Data from the nighttime symptom questions of the Asthma Daily Symptom Diary 
(ADSD) will be used in separate analyses to explore psychometric properties of the 
ADSD (Section 2.1).

Type I Error management plan has been changed to implement a fixed sequence 
method.  The revised testing hierarchy has been specified in Section 4.4.
Additional minor changes have been made to improve clarity and consistency.


MSTT1041A—Genentech, Inc.
3/Statistical Analysis Plan GB39242
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 5
2.
STUDY DESIGN........................................................................................... 5
2.1
Outcome Measures ................................................................. 7
2.1.1
Primary Efficacy Endpoint........................................................ 7
2.1.2
Secondary Efficacy Endpoints................................................. 7
2.1.3
Exploratory Efficacy Endpoints................................................ 8
2.1.4
Safety Endpoints ..................................................................... 8
2.1.5
Pharmacokinetic Endpoint....................................................... 9
2.1.6
Exploratory Biomarker Endpoints ............................................ 9
2.1.7
Exploratory Health Status Endpoints....................................... 9
2.2
Determination of Sample Size ................................................. 9
2.3
Analysis Timing and Unblinding .............................................. 9
2.4
Data Included in Week 54 Data Cut...................................... 10
3.
STUDY CONDUCT..................................................................................... 10
3.1
Randomization Issues ........................................................... 10
3.2
Data Monitoring ..................................................................... 11
4.
STATISTICAL METHODS .......................................................................... 11
4.1
Analysis Populations ............................................................. 11
4.1.1
Modified Intend-to-Treat Population ...................................... 11
4.1.2
Safety-Evaluable Population.................................................. 12
4.1.3
Run-In Safety-Evaluable Population...................................... 12
4.2
Definition of Baseline............................................................. 12
4.3
Analysis of Study Conduct..................................................... 13
4.4
Analysis of Treatment Group Comparability .......................... 13
4.5
Efficacy Analysis.................................................................... 13
4.5.1
Primary Efficacy Endpoint...................................................... 16
4.5.2
Secondary Efficacy Endpoints............................................... 17
4.5.3
Exploratory Efficacy Endpoints.............................................. 22
4.5.4
Sensitivity Analyses............................................................... 24


MSTT1041A—Genentech, Inc.
4/Statistical Analysis Plan GB39242
4.5.5
Subgroup Analyses ............................................................... 26
4.5.6
Biomarker Analyses............................................................... 27
4.6
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 28
4.7
Safety Analyses..................................................................... 29
4.7.1
Exposure to Study Medication............................................... 30
4.7.2
Adverse Events ..................................................................... 30
4.7.3
Laboratory Data..................................................................... 31
4.7.4
ECG Results.......................................................................... 31
4.7.5
Vital Signs.............................................................................. 32
4.8
Missing Data.......................................................................... 32
4.9
Interim Analyses .................................................................... 32
5.
REFERENCES ........................................................................................... 33
LIST OF TABLES
Table 1
Fixed Sequence Testing Hierarchy ............................................ 15
Table 2
Cutoff Values for Summary of Vital Signs ................................... 32
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 7
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 34
Appendix 2
Schedule of Assessments........................................................... 46
Appendix 3
Schedule of Additional Pharmacokinetic Samples for 
Selected Patients........................................................................ 50
Appendix 4
Scoring of the St. George’s Respiratory Questionnaire 
(SGRQ)....................................................................................... 51
Appendix 5
Definition of Asthma Exacerbation for Inclusion Criteria and 
Reporting of Adverse Events ...................................................... 56


MSTT1041A—Genentech, Inc.
5/Statistical Analysis Plan GB39242
1.
BACKGROUND
The purpose of this document is to provide details of the planned analyses for 
Study GB39242.  The primary focus of this Statistical Analysis Plan (SAP) is on analyses 
of complete data from the first 54 weeks of the study, which includes the 2week 
single-blind placebo run-in as well as the 52week double-blind treatment period.  Such 
analyses are described in the main body of this document and will be performed after all 
patients have completed 54 weeks in the study or discontinued early, and all 
corresponding data have been entered into the database, reviewed, and verified.  The 
16week follow-up period of the study may be ongoing at the time of the 54-week 
analysis. No changes to the SAP will be allowed at the time of or subsequent to the 
54-week primary analysis.
The analyses specified in this document supersede the high-level analysis plan 
described in the protocol.
2.
STUDY DESIGN
Study GB39242 is a Phase IIb, randomized, placebo-controlled, double-blind, 
multicenter, multi-arm study of MSTT1041A compared with placebo as add-on therapy in 
patients with severe, uncontrolled asthma who are receiving medium- or high-dose 
inhaled corticosteroids (ICS) therapy and at least one of the following additional
controller medications:  longacting -agonist, leukotriene modifier, long-acting 
muscarinic antagonist, or long-acting theophylline preparation.  Patients must have 
evidence of uncontrolled disease consisting of an Asthma Control Questionnairefive 
items (ACQ-5) score of1.5 and at least one symptom of asthma that is not controlled 
(nighttime awakening 1 time/week and/or short-acting rescue therapy
use2 days/week).  Patients requiring use of systemic corticosteroids (oral, intravenous, 
or intramuscular) or biologic therapy (e.g., anti-Immunoglobulin E [IgE] or 
antiinterleukin-5) at screening were excluded from the study.
The study consists of a 2to 4week screening period, a 2week single-blind placebo 
run-in period, a 52week double-blind treatment period, and a 16week safety follow-up 
period concluding with the end-of-study visit at Week 70 (see Figure 1). At the run-in 
visit (Week 0), scheduled for approximately 2 weeks prior to the randomization visit 
(Week 2), patients who met enrollment criteria for the run-in period received one 
single-blind dose of placebo to allow for evaluation of unexpected variability in asthma 
control.  At the randomization visit, patients underwent further assessments to determine 
eligibility for randomization to the doubleblind treatment period.  The 52week 
double-blind treatment period begins with the randomization visit (Week 2) and ends 
with the Week 54 visit.  Patients who experienced unexpected variability in asthma 
control during the run-in period, as demonstrated by change in forced expiratory volume 
in 1 second (FEV1) and/or fractional exhaled nitric oxide (FeNO), were not eligible for 


MSTT1041A—Genentech, Inc.
6/Statistical Analysis Plan GB39242
randomization into the 52-week double-blind treatment period.  Additional details are 
provided in the study protocol.
Eligible patients were randomized in a 1:1:1:1 ratio to receive MSTT1041A at one of 
three doses (70, 210, or 490 mg) or placebo.  Enrollment caps were utilized to ensure 
adequate power for biomarker subgroup analysis based upon blood eosinophil status at 
visit 1 (300, 300 cells/µL).  The randomization was conducted such that 
approximately 30 patients per arm will have eosinophil-high status and approximately 
95 patients per arm will have eosinophil-low status.  Study drug is administered as four 
SC abdominal injections at the randomization visit (Week 2), Week 6, and every 4 weeks 
thereafter through Week 50.
Safety and efficacy, as well as pharmacokinetic (PK) and pharmacodynamic (PD)
measures, are assessed throughout the double-blind treatment period, as described in 
the protocol and detailed in the Schedule of Assessments (see Appendix 2).  The 
primary efficacy endpoint is the incidence of asthma exacerbations during the 52week 
double-blind treatment period (Week 2 through Week 54).
All patients will be followed for 20 weeks after the last dose of study treatment. The 
20 weeks include 4 weeks after the final dose in the double-blind treatment period and 
16 weeks in the safety follow-up period.  Assessments for the safety follow-up period are 
detailed in the Schedule of Assessments (see Appendix 2).
All patients who discontinue study drug early during the double-blind treatment period 
are asked to continue with the study assessments in the double-blind treatment period 
and then complete the safety follow-up period.  Patients who are unable or unwilling to 
continue with assessments in the double-blind treatment period complete an early
termination visit and then enter the safety follow-up period.
The study design is depicted in Figure 1.


MSTT1041A—Genentech, Inc.
7/Statistical Analysis Plan GB39242
Figure 1
Study Schema
ICSinhaled corticosteroid; Q4Wevery 4 weeks; SCsubcutaneous.
2.1
OUTCOME MEASURES
2.1.1
Primary Efficacy Endpoint
The primary efficacy endpoint is as follows:

Incidence of asthma exacerbations from baseline through Week 54, with asthma 
exacerbation defined as new or increased asthma symptoms (wheezing, coughing, 
dyspnea, chest tightness, and/or nighttime awakenings due to these symptoms) that 
result in one or both of the following:
o
Hospitalization or an emergency department visit with administration of 
systemic corticosteroids treatment
o
Treatment of systemic corticosteroids for3 days or a long-acting depot 
corticosteroid preparation with a therapeutic effectiveness of3 days
2.1.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

Absolute change in pre-bronchodilator FEV1 (liters) from baseline to Week 54

Time to first asthma exacerbation during the 52-week double-blind treatment period

Achievement of improvement Standardized Asthma Quality-of-Life Questionnaires
(AQLQS) score, defined as an increase of0.5 points from baseline to Week 54

Achievement of improvement in ACQ-5 score at Week 54, defined as a decrease 
of 0.5 points from baseline to Week 54

Absolute change in patient-reported use of shortacting rescue therapy from 
baseline to Week 54


MSTT1041A—Genentech, Inc.
8/Statistical Analysis Plan GB39242

Proportion of weeks without patient-reported asthma-related nighttime awakenings 
from baseline through Week 54

Absolute change in patient-reported daytime asthma symptom severity as measured 
by the Asthma Daily Symptom Diary (ADSD) from baseline to Week 54
2.1.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are as follows:

Incidence of asthma exacerbations from baseline through Week 54, with asthma 
exacerbation defined as in Appendix 5

Incidence of severe asthma exacerbations from baseline through Week 54, with 
severe asthma exacerbation defined as asthma symptoms requiring hospitalization 
or resulting in death attributed to asthma

Incidence of asthma exacerbations from randomization visit through Week 70

Relative change in pre-bronchodilator FEV1 (liters) from baseline to Week 54

Absolute change in pre-bronchodilator FEV1 (percentage predicted) from baseline to 
Week 54

Absolute change in pre-bronchodilator FEV1 (liters) from baseline to Week 70

Achievement of improvement in St. George’s Respiratory Questionnaire (SGRQ) 
score, defined as a decrease of4 points from baseline to Week 54

Achievement of improvement in ACQ-7 score, defined as a decrease of0.5 points
from baseline to Week 54

Clinician's global impression of change (CGIC) in patient's asthma symptoms, as 
assessed through use of the CGIC, from baseline to Week 26 and Week 54

Incidence of asthma exacerbations from baseline through Week 54 within each of 
the eosinophil-high (300 cells/µL) and eosinophil-low (300 cells/µL) groups

Absolute change from baseline to Week 54 in pre-bronchodilator FEV1 (liters) within 
each of the eosinophil-high (300 cells/µL) and eosinophil-low (300 cells/µL) 
groups

Incidence of asthma exacerbations from baseline through Week 54 by IL1RL1
genotype

Absolute change in pre-bronchodilator FEV1 (liters) from baseline to Week 54 by 
IL1RL1 genotype
2.1.4
Safety Endpoints
The safety endpoints are as follows:

Incidence and severity of adverse events, with severity determined through use of 
the World Health Organization-Adverse Drug Reaction Terminology (WHO-ART)

Change from baseline in vital signs, ECGs, and clinical laboratory results

Incidence of anti-drug antibodies (ADAs)


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2.1.5
Pharmacokinetic Endpoint
The PK endpoint is as follows:

Serum concentration of MSTT1041A at specified timepoints
2.1.6
Exploratory Biomarker Endpoints
The key exploratory biomarker endpoints are as follows:

Relative change in FeNO and blood eosinophils from baseline through Week 54

Absolute levels of the soluble form of ST2-(sST2) in blood from baseline through 
Week 70
2.1.7
Exploratory Health Status Endpoints
The exploratory health status endpoint is as follows:

Change in health status utility as assessed by the EuroQol 5-Dimension 
Questionnaire (EQ-5D-5L) from baseline to Week 54
2.2
DETERMINATION OF SAMPLE SIZE
A total of 502 patients were randomly allocated in a 1:1:1:1 ratio to receive one of three 
doses of MSTT1041A or placebo. This sample size provides approximately 80% power 
to detect a 40% reduction in the annualized asthma exacerbation rate (AER) between 
one MSTT1041A arm and the placebo arm, assuming 0.63 exacerbations per patient per 
year in the placebo arm, no Poisson over dispersion, a 15% dropout rate, and a 
two-sided significance level () of 0.05.
Enrollment caps are utilized to ensure adequate power for biomarker subgroup analysis 
based upon blood eosinophil status at visit 1.  Approximately 30 eosinophil-high patients 
(300 cells/µL) per arm and approximately 95 eosinophil-low patients (300 cells/µL) 
per arm are randomly allocated.  The sample size provides approximately 80% power to 
detect a 50% reduction in the annualized AER for the subgroup of eosinophil-high 
patients assuming 1.0 exacerbations per patient per year in the placebo arm, a 15% 
dropout rate, a two-sided significance level of 0.15, and 30 patients in each treatment 
arm having eosinophil-high status.  The sample size also provides approximately 67% 
power to detect a 35% reduction in the annualized AER for the subgroup of 
eosinophil-low patients, assuming 0.5 exacerbations per patient per year in the placebo 
arm, no Poisson over dispersion, a 15% dropout rate, a two-sided significance level of 
0.15, and 95 patients in each treatment arm having eosinophil-low status.
2.3
ANALYSIS TIMING AND UNBLINDING
Analysis of data from the 52-week double-blind treatment period of the study, defined as 
the time of randomization (Week 2) through the Week 54 visit, will be performed when all 
patients either (i) have completed the Week 54 visit, (ii) have discontinued treatment 
early from the 52week double-blind treatment period of the study but completed 
follow-up visits up to 52weeks post-randomization, or (iii) have withdrawn from the 


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study prior to Week 54, and all data from the first 54 weeks of the study are in the 
database and have been reviewed.
At the time of the primary analysis, the Sponsor personnel who are analyzing data from 
the first 54 weeks of the study will be unblinded to treatment assignment.  This includes 
personnel directly involved in the statistical analyses and programming activities as well 
as Sponsor personnel from other functions (e.g., Clinical Science, Safety Science, 
Clinical Pharmacology, and Regulatory Affairs) who will be involved in assessing, 
summarizing, and interpreting the data.
The analysis of complete data for the study, including data from the safety follow-up 
period, will be performed when all patients have either completed the safety follow-up 
period or have discontinued early from the study, all data from the study are in the 
database, and the database is locked.
Aggregate results of the primary analysis, summarized by treatment arm and potentially 
biomarker group, may be reported to the public before completion of the study.  However, 
patients and study site personnel will remain blinded to individual treatment assignment 
until after the study is completed (after all patients have either completed the safety 
follow-up period or discontinued early from the study), the database is locked, and the 
study analyses are final.
2.4
DATA INCLUDED IN WEEK 54 DATA CUT
The following data will be included in the Week 54 data cut:

For patients randomized to the 52-week double-blind treatment period: All 
screening, run-in and post-baseline data with a clinical date (i.e., 
administration/assessment/onset/start date) on or before the date of randomization 
to Week 54 will be included.

For patients not randomized to the 52-week double-blind treatment period:  All 
screening and run-in data with a clinical date (i.e., 
administration/assessment/onset/start date).
The Week 54 data cut will include all data regardless of the type of study visit at which it 
was collected. This may include data collected at unscheduled visits, dosing termination 
visits, early termination visits, or safety follow-up visits, if the visit date was on or before 
the Week 54 data cutoff date.
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
Following successful completion of the run-in period, at the Week 2 visit, patients were
randomly allocated to one of four treatment arms (MSTT1041A 70 mg, MSTT1041A 
210 mg, MSTT1041A 490 mg, or placebo) in a 1:1:1:1 ratio through an interactive voice 
or web-based response system (IxRS).  Randomization was stratified by blood 


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eosinophil status at visit 1 (150, 150 to 300, 300 cells/µL), number of documented 
asthma exacerbations (as defined in Appendix 5) in the previous 12 months (1-2,3), 
total daily ICS dose at visit 1 (1000 µg,1000 µg of fluticasone proportionate or 
equivalent), and country.  A dynamic randomization method is used to obtain an 
approximately 1:1:1:1 ratio between the four treatment arms and within each stratum.
During both the run-in and the 52week double-blind treatment periods, the IxRS will 
make study-drug kit assignments.  Patient randomization and the study-drug kit 
assignments will be verified on an ongoing basis by an external and independent data 
coordinating center (iDCC). The iDCC independently reviews the logs to ensure that 
randomization and kit assignments are conducted correctly by the IxRS.
3.2
DATA MONITORING
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct on an ongoing basis.  Members of the iDMC are external to the Sponsor and 
follow procedures that are detailed in a Charter that outlines the iDMC roles and 
responsibilities.  The iDMC will meet approximately every 3 months to review unblinded 
safety and study conduct data prepared by the iDCC.  In addition, the iDMC or the 
Sponsor may request ad hoc reviews at any time to address potential safety concerns.
Safety monitoring reviews include unblinded evaluation of all adverse events, serious 
adverse events, adverse events of special interest, major protocol deviations, ECG, and 
laboratory data.  If the iDMC deems a benefit-risk assessment necessary, the iDMC may 
also review unblinded efficacy data.  The iDMC may recommend stopping the study 
early for safety reasons.  However, the iDMC may not recommend stopping the study 
early for positive efficacy or solely for futility.  Formal stopping guidelines for assessing 
safety or the balance between the risks and benefits related to continuing the study will 
not be provided by the Sponsor.  The iDMC will use its collective judgement to 
recommend early termination of the study if the data indicate an unacceptable safety 
profile.  Details will be provided in the iDMC Charter.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
Three analysis populations are defined for this study:  the modified intend-to-treat (mITT)
population, the safety-evaluable population, and the runin safety-evaluable population.
4.1.1
Modified Intend-to-Treat Population
The mITT population will include all patients who were randomly allocated and received 
at least one dose of study drug (MSTT1041A or placebo) during the 52week 
double-blind treatment period (Week 2 through Week 54).  For analyses based on this 
population, patient treatment groups will be defined according to the treatment that was 
assigned at randomization (placebo, MSTT1041A 70 mg, MSTT1041A 210 mg, or 
MSTT1041A 490 mg).


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4.1.2
Safety-Evaluable Population
The safety-evaluable population will include all patients who were randomly allocated
and received at least one dose of study drug (MSTT1041A or placebo) during the 
52week double-blind treatment period (Week 2 through Week 54) with treatment 
groups defined according to the actual treatment received.
Because each patient can receive up to 13 doses of study drug during the 52week 
double-blind treatment period, the treatment received will be defined as the study 
treatment (placebo, MSTT1041A 70 mg, MSTT1041A 210 mg, or MSTT1041A 490 mg) 
most frequently given to the patient during the double-blind treatment period.  In the 
event that this is not unique, treatment received will be defined as the highest of the 
most frequently given dose levels (e.g., a patient who receives 1 dose of placebo and 
1 dose of MSTT1041A 70 mg would be assigned to the MSTT1041A 70 mg treatment 
group for analyses based on the safety-evaluable population).
It is expected that most patients will receive their assigned treatment at all dosing 
timepoints and that only a small number of dosing errors, if any, will occur.  Nonetheless, 
each dosing error will be reported as a major protocol deviation and reviewed in 
conjunction with the corresponding patient’s safety data to assess for any impact on the 
overall safety conclusions.
4.1.3
Run-In Safety-Evaluable Population
The runin safety-evaluable population will include all patients who received the 
single-blind placebo dose during the run-in period (Week 0 treatment), regardless of 
whether or not the patient is randomly allocated into the double-blind treatment period.  
For safety analyses based on this population, only events that occur during the 2-week 
run-in period will be included.  As placebo should be the only study drug administered 
during the run-in period, all patients will be grouped together for analyses based on this 
population.
In the rare event that a patient mistakenly receives MSTT1041A rather than placebo 
during the run-in visit, each dosing error will be reported as a major protocol deviation 
and reviewed in conjunction with the corresponding patient’s safety data to assess for 
any impact on the overall safety conclusions.
4.2
DEFINITION OF BASELINE
Baseline is defined as the last available pre-treatment value taken on or before the day 
of randomization (Week 2 visit) for all assessments, with the exception of the following 
efficacy endpoints: patient-reported use of short-acting rescue therapy, and 
patient-reported daytime asthma symptom severity as measured by Asthma Daily 
Symptom Diary (ADSD).  For these outcome measures, details for derivation of baseline 
values can be found in Section 4.5.2.


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Baseline measurements will be used for the summary of demographic characteristics, as 
well as for all change-from-baseline analyses of efficacy, safety, and PD endpoints
(including change from baseline in FEV1, CGIC, blood eosinophil count, and FeNO, and 
improvement from baseline in AQLQ(S), ACQ-5, SGRQ, ACQ-7).
For endpoints that are defined in terms of change from baseline or improvement from 
baseline, patients who do not have a baseline measurement will be excluded from the
analyses.
4.3
ANALYSIS OF STUDY CONDUCT
The number of patients randomized will be tabulated by region, country, study site, and 
treatment arm.  Patient disposition (the number of patients receiving the single-blind 
placebo dose during run-in, randomly allocated, receiving at least one dose of study 
drug during the double-blind treatment period, completing study treatment during the 
double-blind treatment period, and completing study visit assessments through Week 54) 
and time on study will be tabulated by treatment arm.  Reasons for premature 
discontinuation from study treatment and reasons for premature discontinuation from the 
study prior to Week 54 will be summarized.  Eligibility criteria deviations, dosing errors, 
and other major protocol deviations will be summarized.
4.4
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics including but not limited to age, sex, race, 
ethnicity, blood eosinophil count, number of exacerbations in the prior year, concomitant 
asthma medication use, pulmonary function, and asthma control (as measured by the 
ACQ-5), will be summarized for the mITT population by treatment arm using descriptive 
statistics.  Exposure to study drug (number of study drug treatments and duration of 
treatment) will be summarized for the double-blind treatment period by treatment arm.
4.5
EFFICACY ANALYSIS
Efficacy analyses will be conducted on the mITT population (see Section 4.1.1), with 
patients grouped according to the treatment assigned at randomization.
Efficacy summaries for the 52week double-blind treatment period will include data from 
patients who discontinued study drug early but continued with study assessments and 
may include data collected at unscheduled visits, early termination visits, or safety 
follow-up visits, if the visit date occurred within 52-weeks after the randomization visit.  
For patients completing the Week 54 visits after the schedule Week 54 windows, their 
Week 54 visits will be considered out-of-window and the corresponding data will be 
treated as missing.
Comparisons of Interest
Comparisons of efficacy will be performed between each MSTT1041A dose level and 
the placebo group.


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Thus, there will be three comparisons:

MSTT1041A 70 mg with placebo 

MSTT1041A 210 mg with placebo

MSTT1041A 490 mg with placebo
Hypothesis testing and estimation of treatment effects will be performed with regression 
models that are fit using data from all four treatment arms and which include three 
indicator variables to characterize the three treatment comparisons described above.
Type I Error Management
Type I error will be controlled using a fixed sequence testing procedure at the 5% level 
of significance (two-sided) for primary and secondary efficacy endpoints.   For each 
endpoint the testing procedure will proceed with comparisons from highest to lowest 
MSTT1041A dose level versus placebo (see Table 1) in the order specified below.




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Covariate Adjustment
Unless otherwise noted, analyses of efficacy endpoints (primary, secondary, and 
exploratory) will be adjusted for each of the following covariates:

Blood eosinophil level at visit 1 (150,150 to300,300 cells/µL)

Number of asthma exacerbations requiring use of systemic corticosteroids within the 
12 months prior to study entry (12,3 events)

Total daily ICS dose at visit 1 (1000µg,1000 µg of fluticasone propionate or 
equivalent)

Geographic region (North America [United States, Canada], Latin America 
[Argentina, Mexico, Peru], Central and Eastern Europe [Bulgaria, Czech Republic, 
Poland, Romania, Russia, Serbia, Ukraine], Western Europe plus Rest of World 
[Australia, Belgium, France, Germany, New Zealand, South Africa, South Korea]).
No missing data of these baseline covariates are expected.  Stratification data collected 
in the IxRS system, rather than on the electronic Case Report Forms, will be used.
4.5.1
Primary Efficacy Endpoint
The primary efficacy objective for this study is to evaluate the efficacy of MSTT1041A 
compared with placebo on the basis of the following endpoint:
Incidence of asthma exacerbations from baseline through Week 54, with asthma 
exacerbation defined as new or increased asthma symptoms (wheezing, coughing, 
dyspnea, chest tightness, and/or nighttime awakenings due to these symptoms) that 
result in one or both of the following:

Hospitalization or emergency department visit with administration of systemic 
corticosteroid treatment

Treatment with systemic corticosteroids for3 days or a long-acting depot 
corticosteroid preparation with a therapeutic effectiveness of3 days
The estimand of interest, i.e., the mITT estimand, is the reduction in the rate of asthma 
exacerbations over 52 weeks (for MSTT1041A relative to placebo) for all randomized 
patients who received at least one dose of study drug, regardless of adherence to the 
assigned study treatment or to the protocol.  Because the protocol specifies that patients 
who discontinue study drug early continue with study assessments, an analysis of all 
observed exacerbation data will lead to a reasonable estimate of the mITT estimand.  
However, some data may be missing because of early study discontinuation, and 
sensitivity of the primary analysis to missing data assumptions will be assessed by 
sensitivity analyses per Section 4.5.4.
For each patient, the time period at risk will be defined as follows:

From the date of randomization to date of the actual Week 54 visit for patients who 
completed the double-blind treatment period


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
From the date of randomization to the date of last assessment during the 
double-blind treatment period for patients who complete or discontinue from the 
study early
All protocol-defined asthma exacerbations with an onset date during this time period at 
risk will be included in the primary analysis.  For each patient, the time at risk (in years) 
will be computed as the duration of this time period (last day minus first day [in days] 
plus1) divided by 365.25.  Unadjusted rates of asthma exacerbations will be estimated 
by dividing the total number of protocol-defined asthma exacerbations observed during 
the time at risk by the total time at risk (in years) for each treatment arm.
The rate of asthma exacerbations will be compared between each active treatment arm 
and the placebo arm with the use of a Poisson regression model with over-dispersion.  
The primary analysis will be on the basis of observed exacerbations, with no imputation 
for premature study discontinuation.  The Poisson regression model will include terms 
for treatment arm (three indicator variables, corresponding to the three treatment arms) 
and the baseline covariates described in Section 4.5.  Patient time at risk will be used as 
an offset term in the model.  The dispersion parameter will be estimated by Pearson’s 2
statistic divided by its degrees of freedom.
Rates of asthma exacerbations adjusted for specified baseline covariates 
(see Section 4.5) will be estimated for each treatment arm with the use of the Poisson 
regression model.  The ratio of exacerbation rates (for each MSTT1041A arm compared 
with the placebo arm) will be estimated from the Poisson regression model along with 
associated 95% CIs and p-values.  The absolute difference in the exacerbation rates (for 
each MSTT1041A arm compared with the placebo arm, expressed as events per year) 
will also be provided, along with the associated 95% CIs.
See Sections 4.5.4, 4.5.5, and 4.5.6 for sensitivity, subgroup, and additional biomarker 
analyses that will be performed for the primary efficacy endpoint, respectively.
4.5.2
Secondary Efficacy Endpoints
Time to First Asthma Exacerbation
A Cox proportional hazards regression model will be used to estimate the hazard ratio 
comparing each MSTT1041A treatment arm with the placebo arm with respect to time to 
the first asthma exacerbation.  The model will include treatment arm and baseline
covariates as described in Section 4.5.  Patients who do not experience a 
protocol-defined asthma exacerbation during the 52-week double-blind treatment period
will be censored at the end of their time at risk (see Section 4.5.1).  Point estimates, 
95% CIs, and p-values for the treatment effect (MSTT1041A vs. placebo) will be 
calculated for each MSTT1041A dose level based on the model.


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Pre-Bronchodilator Forced Expiratory Volume in 1 Second (Liters)
The absolute change in pre-bronchodilator FEV1 from baseline will be summarized by 
treatment arm and timepoint.  The difference in mean absolute change in 
pre-bronchodilator FEV1 at Week 54 from baseline between each MSTT1041A treatment 
arm and the placebo arm will be estimated using a mixed model for repeated measures
(MMRM).  The model will use absolute change from the randomization visit as the 
response variable and include terms for treatment arm, study visit, treatment arm by 
study visit interaction, baseline FEV1 (as a continuous variable) as well as its interaction 
with study visit, and the baseline covariates as described in Section 4.5.  Study visit will 
be included as a categorical variable.  An unstructured covariance matrix will be 
specified to model the within-subject errors.  Point estimates, 95% CIs, and p-values for 
the treatment effect (MSTT1041A vs. placebo) will be calculated for each MSTT1041A
dose level on the basis of the model for all study visits, including Week 54.
In addition to evaluating the treatment benefit at Week 54, the absolute change from 
baseline in pre-bronchodilator FEV1 over time will be characterized in order to establish 
the time of onset of sustained FEV1 effect.  Considering each dose level separately, if a
statistically significant difference between MSTT1041A and placebo is observed at 
Week 54, then nominal tests for significance will be performed sequentially at each prior
planned timepoint for which FEV1 was assessed (working backward), continuing until the 
p-value for a timepoint is0.05.  This procedure will be used to determine the earliest 
timepoint at which significance is observed at that timepoint and at all subsequent 
timepoints up to Week 54 (comparing MSTT1041A with placebo), and considered the 
time of onset of sustained FEV1 improvement.
See Sections 4.5.4, 4.5.5, and 4.5.6 for sensitivity, subgroup, and additional biomarker 
analyses, respectively, that will be performed for the secondary endpoint of absolute 
change in pre-bronchodilator FEV1 from the randomization visit at Week 54.
Asthma Quality of Life Questionnaire (Standardized) 
Asthmaspecific health-related quality of life will be measured by the AQLQ(S) scores.  
With this scale, higher scores indicate better health-related quality of life and 0.5 points 
is considered the minimally important difference (MID).
The AQLQ(S) domain scores will be calculated from the individual question responses 
as follows:
Symptoms(Items 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30)/12
Activity Limitation(Items 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32)/11
Emotional Function(Items 7, 13, 15, 21, 27)/5
Environmental Stimuli(Items 9, 17, 23, 26)/4


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The overall healthrelated quality of lifescore will be calculated from the individual 
question responses as follows and will be summarized by treatment arm and timepoint 
for each biomarker group.
AQLQ(S) Overall score(Items 1 to 32)/32
The proportion of patients who achieve a clinically meaningful improvement in AQLQ(S)
(improvement of0.5 points from baseline) at Week 54 will be summarized by treatment 
group and timepoint.  AQLQ(S) at randomization visit (Week 2) will be used as the 
baseline AQLQ(S) score.  A logistic regression model, with terms for treatment group, 
baseline AQLQ(S), and the baseline covariates described in Section 4.5 will be used to 
compare MSTT1041A with placebo.  For patients without a Week 54 assessment of 
AQLQ(S), the Week 26 score will be used.  Patients without a post-randomization 
assessment (Week 26 or Week 54) will be excluded from the analysis.  Point estimates, 
95% CIs, and p-values for the treatment difference (MSTT1041A vs. placebo) will be 
calculated for each MSTT1041A dose level.
Considering each dose level separately, if a statistically significant difference between 
MSTT1041A and placebo is observed at Week 54, then a test for significance will be
performed at Week 26.  This procedure will be used to determine the earliest timepoint 
at which significance is observed (comparing MSTT1041A with placebo), and 
considered the time of onset of sustained AQLQ(S) improvement.
Asthma Control Questionnaire
Asthma control, as measured by the ACQ, will be assessed by asking patients to recall 
their experience with asthma during the previous week.  The full ACQ consists of seven 
questions:  five questions related to symptoms (i.e., nighttime awakening, asthma 
symptoms upon awakening in the morning, activity limitation, shortness of breath, and 
wheezing frequency), one question about use of short-acting rescue therapy, and one 
question about FEV1 (to be completed by site staff). The items are scored on a scale 
ranging from 0 (totally controlled) to 6 (extremely poorly controlled).  The items are 
equally weighted.  For the ACQ, higher scores indicate worse control, and 0.5 points is 
considered the MID. The ACQ can be scored two ways: 1) the mean of the five 
symptom-related items (ACQ-5); or 2) the mean of all 7 items (ACQ-7).
The proportion of patients who achieve a clinically meaningful improvement in asthma 
control based on the ACQ-5 (decrease of0.5 points from baseline) will be analyzed 
using the same methodology as described for achievement of improvement from 
baseline at Week 54 in AQLQ(S).  ACQ-5 at randomization visit (Week 2) will be used as 
the baseline ACQ-5 score.
Asthma Rescue Medication Use
Asthma rescue medication use as recorded in the patient’s daily electronic diary (e-Diary)
will be used for analysis.  For each patient, baseline asthma rescue medication use will 
be defined as the proportion of days with rescue medication use over a 14-day period


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prior to the Week 0 visit (i.e. during screening).  Patients must have two consecutive 
compliant weeks during screening in their asthma rescue medication use to have a 
baseline score calculated.  During screening, a patient is compliant in a week if they 
have at least 5 of 7 days of non-missing entries of asthma rescue medication use. The 
baseline proportion of days with asthma rescue medication use will first be calculated 
using the two consecutive screening compliant weeks prior to the run-in visit.  However, 
if the condition of two consecutive screening compliant weeks does not hold in the 14 
days prior to the run-in visit, the window will be shifted back by 7 days until a period of 
two consecutive screening compliant weeks is identified.  As one of the inclusion criteria 
for patients to enter the run-in period is completion of the e-Diary for at least 5 of 7 days 
during each of 2 consecutive weeks during the screening period, i.e., patients having two 
consecutive screening compliant weeks, missing baseline score is not expected.  In the 
rare event that a patient does not have a valid baseline score, the patient will be 
excluded from this analysis. 
Although rescue medication is to be recorded each morning and each evening, any day 
on which at least one entry is collected will be included in analyses.  For each patient 
and monthly post-baseline assessment timepoint (i.e., Week 6, Week 10, …Week 54), 
the post-baseline asthma medication use for that timepoint will be defined as the 
proportion of days with rescue medication use over the 28 days on or prior to the 
timepoint (inclusive).  Patients must have recorded their asthma rescue medication use 
at least once a day for at least 14 days during a 28-day interval to have a score 
calculated for the respective timepoint.  Missing entries will be excluded from the 
calculation.  For example, if a patient has only recorded rescue medication use for 20 of 
the 28 days, then the proportion of days will be calculated out of the 20 days with an 
entry.
The absolute change from baseline in the proportion of days with asthma rescue 
medication use will be summarized by treatment arm and timepoint.  The absolute 
difference in mean change in proportion of days of rescue medication use from 
randomization at Week 54 between each treatment arm and the placebo arm will be 
estimated on the basis of an MMRM analysis.  The model will use absolute change from 
baseline as the response variable and include terms for treatment arm, study visit, 
treatment arm by study visit interaction, baseline asthma rescue medication use (as a 
continuous variable) as well as its interaction with study visit, and the baseline covariates 
described in Section 4.5.  Study visit will be included as a categorical variable.  An 
unstructured covariance matrix will be specified to model the within-subject errors.  Point 
estimates, 95% CIs, and p-values for the treatment difference (MSTT1041A vs. placebo) 
will be calculated for each MSTT1041A dose level based on the model for all study visits 
including Week 54.
Asthma-Related Nighttime Awakenings
Nighttime awakenings, as recorded each morning in the patient’s daily e-Diary, will be 
used for analysis. For each patient, the proportion of weeks without a nighttime 


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awakening from baseline through Week 54 will be calculated. The randomization visit 
(Week 2) will be used as baseline.
From the randomization visit, the subsequent weeks will be counted by a 7-day window 
until Week 54 is reached.  For each 1-week period after randomization visit, if there 
are 4 or more morning diaries with missing entries, the 1-week period is considered a 
non-compliant week and the corresponding value will be considered as missing. These 
missing values will not be imputed, and these missing weeks will not be included in the 
denominator when calculating the proportion of weeks.  However, if there 
are3 morning diaries with missing entries during a 1-week period but one of the 
available entries for the 1-week period reports a nighttime awakening, this 1-week period 
will be included in the calculation.
The proportion of weeks without a nighttime awakening due to asthma will be 
summarized by treatment arm. The absolute difference in mean proportion between 
each MSTT1041A dose level and the placebo arm will be estimated on the basis of an 
analysis of variance model.  The model will use the proportion of weeks without a 
nighttime awakening due to asthma as the response variable and include terms for 
treatment arm and the baseline covariates described in Section 4.5. Point estimates, 
95% CIs, and p-values for the treatment difference (MSTT1041A vs. placebo) will be 
calculated for each MSTT1041A dose level.
Daytime Asthma Symptom Severity
Daytime asthma symptom severity will be assessed by patient ratings of asthma 
symptoms each evening, as recorded in the ADSD on their e-Diary.
The daily daytime symptom scores are calculated each day as an average of the six 
core evening diary symptoms: difficulty breathing, wheezing, shortness of breath, chest 
tightness, chest pain and cough.  Each question is scored from the scale of 0 to 10, in 
which higher scores indicate worse symptoms.  The daytime symptom score for each 
timepoint is then calculated as a weekly average of the 7 individual average daily scores. 
Daily scores will only be calculated if data for 4 or more items per day are available.
Daily scores will be averaged over the previous week prior to each scheduled visit (i.e., 
7 days prior to Week 54 visit). For each week after randomization visit, if there are3 
days with missing scores out of the 7 days, the week is considered a non-compliant 
week and the average score for the week will be considered as missing. These missing 
values will not be imputed but will be handled directly by the MMRM model.
The baseline value will be derived based on a 2-week screening period prior to the 
Week 0 visit. Patients must have two consecutive compliant weeks during screening to 
have a baseline score calculated.  During screening, a patient is compliant in a week if 
they have at least 5 of 7 days of non-missing scores.  The baseline score will first be 
calculated using the two consecutive screening compliant weeks prior to the run-in visit.  


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However, if the condition of two consecutive screening compliant weeks does not hold in 
the 14 days prior to the run-in visit, the window will be shifted back by 7 days until a 
period of two consecutive screening compliant weeks is identified.  Patients without a 
‘valid’ baseline score will be excluded from the analysis.
The absolute change from baseline in daytime symptom severity scores will be 
summarized by treatment arm and timepoint.  The absolute difference in mean change 
in daytime symptom severity scores from baseline at Week 54 between each treatment 
arm and the placebo arm will be estimated on the basis of an MMRM analysis.  The 
model will use absolute change from baseline as the response variable and include 
terms for treatment arm, study visit, treatment arm by study visit interaction, baseline 
symptom score as well as its interaction with study visit, and the baseline covariates 
described in Section 4.5.  Study visit will be included as a categorical variable.  An 
unstructured covariance matrix will be specified to model the within-subject errors.  Point 
estimates, 95% CIs, and p-values for the treatment difference (MSTT1041A vs. placebo) 
will be calculated for each MSTT1041A dose level based on the model for all study visits 
including Week 54.
4.5.3
Exploratory Efficacy Endpoints
Asthma Exacerbation as Defined in Appendix 5
The incidence of asthma exacerbations, defined as in Appendix 5, will be analyzed with 
the use of the same methodology as described for the primary endpoint 
(see Section 4.5.1).
Severe Asthma Exacerbations
The incidence of severe asthma exacerbations, defined as asthma symptoms requiring 
hospitalization or resulting in death attributed to asthma, will be analyzed with the use of 
the same methodology as described for the primary endpoint (see Section 4.5.1).
Asthma Exacerbations through Week 70
The incidence of severe asthma exacerbations from randomization through Week 70 will 
be analyzed with the use of the same methodology as described for the primary 
endpoint (see Section 4.5.1).
Relative Change in Pre-Bronchodilator Forced Expiratory Volume in 
1 Second (Liters)
For each patient and timepoint, the relative change in pre-bronchodilator FEV1 will be 
defined as the absolute change from the baseline in FEV1 (liters) divided by the FEV1
(liters) at baseline.  The relative change in pre-bronchodilator FEV1 from the baseline will 
be analyzed using the same methodology as described for the secondary endpoint of 
absolute change in pre-bronchodilator FEV1 from baseline to Week 54, except that 
relative change from baseline will be the response variable.


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Pre-Bronchodilator Forced Expiratory Volume in 1 Second (Percentage 
Predicted)
The absolute change in pre-bronchodilator FEV1 (percentage predicted) from baseline to 
Week 54 will be analyzed using the same methodology as described for the secondary 
endpoint of absolute change in pre-bronchodilator FEV1 from baseline to Week 54.
Pre-Bronchodilator Forced Expiratory Volume in 1 Second (Liters) at
Week 70
The absolute change in pre-bronchodilator FEV1 from baseline to Week 70 will be 
analyzed using the same methodology as described for the secondary endpoint of 
absolute change in pre-bronchodilator FEV1 from baseline to Week 54.
St. George’s Respiratory Questionnaire
The SGRQ is a 50-item respiratory-specific quality-of-life questionnaire initially 
developed and validated for use in chronic obstructive pulmonary disease.  It includes 
questions that assess the impact of disease on symptoms, activity, and functionality.  
The symptom scale assesses the severity of respiratory symptoms, the activity scale 
examines impairment in patient activity as a result of respiratory symptoms, and the 
impact scale evaluates effects of respiratory symptoms on overall function and 
well-being.  Each scale is scored from 0 to 100, and a total score represents the 
weighted average of these three components.
Each item in the SGRQ has specific weight (lowest possible weight0, highest100).
Scores for the three scales and total are calculated using the assigned weights. The 
numerator and denominator for the total and each scale are comprised of individual item 
weights, minus specific scale weights. See Appendix 4 for weighting, and 
numerator/denominator calculation details.
Total and scale scores will be calculated as follows:
Total Score100*([item weights)/(maximum total weight])
Symptom Score100*([item 1,2,3,4,5,6,7,8 weights)/(maximum symptom total 
weight])
Activity Score100*([item 11,15 weights)/(maximum activity total weight])
Impact Score100*([item 9,10,12,13,14,16,17 weights)/(maximum impact total 
weight])
The maximum number of missing values that can be tolerated for each scale are as 
follows:

Symptoms: 2

Activity: 4

Impacts: 6


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Missing item weights are subtracted from each scale’s total weight for calculating that 
scale’s score.
The proportion of patients who achieve a clinically meaningful improvement in the SGRQ
(defined as a decrease of4 points from baseline) will be analyzed using the same 
methodology as described for the secondary endpoint of achievement of improvement 
from baseline to Week 54 in AQLQ(S).  SGRQ at randomization visit (Week 2) will be 
used as the baseline score.
Asthma Control Questionnaire
The achievement of improvement from randomization visit in ACQ-7 score at Week 54, 
defined as a decrease of0.5 points, will be analyzed using the same methodology as 
described for the secondary endpoint of achievement of improvement from baseline to 
Week 54 in AQLQ(S).  ACQ-7 at randomization visit (Week 2) will be used as the 
baseline score.
Clinician Global Impression of Change
The CGIC is a single-item assessment of the clinician’s impression of a patient's change 
in asthma symptoms since beginning the 52week double-blind treatment period.  
Change in asthma symptoms is rated on a 7-point scale ranging from very much worse 
to very much improved.
CGIC outcomes will be summarized on the basis of the proportion of patients with an 
outcome at each of the possible levels (i.e., “very much worse” to “very much improved”) 
by treatment arm and timepoint.  The proportion of patients with a “very much improved”
or “much improved” CGIC score at Week 54 will be compared between each 
MSTT1041A arm and the placebo arm with the use of a logistic regression model with 
terms for treatment arm and the baseline covariates as described in Section 4.5. For
patients without a Week 54 assessment, the Week 26 assessment will be used.  
Patients who have missing CGIC scores at both Weeks 26 and 54 will be excluded from 
analysis.
Biomarker Subgroup Analyses
Details about efficacy analyses by eosinophil and IL1RL1 genotype subgroups are 
presented in Section 4.5.6.
4.5.4
Sensitivity Analyses
Sensitivity analyses will be performed to evaluate the robustness of the primary analysis 
results.

Parametric Model.  The primary efficacy endpoint will be re-analyzed using a 
negative binomial regression model, using the same covariates as specified for the 
primary analysis with Poisson regression.  All other elements of the analysis will 
remain the same as in the primary analysis.


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The following analyses will be performed to assess the sensitivity of results to missing 
data assumptions:

Missing Data Assumptions.  The primary endpoint (incidence of asthma 
exacerbations) and all secondary efficacy endpoints (except for time to first asthma 
exacerbation) found to be significant for a given MSTT1041A arm will be 
re-analyzed assuming that missing data is missing not at random, rather than 
missing at random (MAR), via tipping point sensitivity analyses implemented using 
multiple imputation.  In general, imputation models will account for the same 
baseline covariates as used in the earlier described analysis of the endpoint and 
post-baseline outcome data when possible.  Multiple imputed datasets will be 
grouped by a range of missing data assumptions and analyzed according to the 
same analysis models specified in Section 4.5, and the results will be combined for 
each assumption using Rubin’s rules (Barnard and Rubin 1999).  These analyses 
will be implemented as follows:

For continuous secondary endpoints that assess absolute changes from baseline to 
Week 54 (e.g., for pre-bronchodilator FEV1), imputation under the MAR assumption 
will be used to generate multiple datasets with imputed values.  It will be assumed 
that the pattern of missing data in the outcome to be analyzed is monotone.  In the 
event that the missing data do not follow a monotone pattern, multiple imputation 
using Markov chain Monte Carlo methods will be used to partially impute data under 
MAR, thereby converting the dataset to a monotone missing pattern.  After 
imputation to achieve a monotone missing pattern, the remaining missing values will 
be imputed using a regression-based approach in a sequential manner with the use 
of univariate models, separately in each treatment group.  For each visit, a 
regression model based on all patients who have observations (imputed or 
observed) available up to and including this visit will be fitted and used to impute 
missing values at this visit.  All regression-based imputation models will include the 
baseline covariates described in Section 4.5 and prior observed or imputed 
outcomes.

Tipping-point analysis will be implemented by adding (or subtracting) a constant to 
the post-dropout MAR imputed values; a separate will be applied to each 
treatment arm (each MSTT1041A dose level and placebo).  A range of will be 
used to adjust post-dropout imputed values in the MSTT1041A and placebo arms 
independently based on a grid of adjustments.  For each endpoint, the size of the 
will be chosen on the basis of the estimated treatment effect for a given 
MSTT1041A arm compared with placebo from the analyses specified in 
Section 4.5.2.  The range will be chosen to include cases in which dropouts from the 
MSTT1041A arm have worse outcomes than dropouts from the placebo arm.  For 
each endpoint, the resulting point estimates of treatment effect and corresponding 
p-values under each pair of for each MSTT1041A arm and placebo comparison
will be tabulated.

For the primary endpoint (incidence of asthma exacerbations), tipping point analysis 
via multiple imputation of event counts assuming a range of will be performed.  
Event counts will be imputed at the patient level for the unobserved period between 
the last study visit and Week 54 for patients who discontinued study assessments 


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early.  An event count corresponding to each unobserved period will be imputed by 
first fitting a negative binomial generalized linear model to the observed data and 
sampling from the posterior distribution of the model parameter estimates.  These 
sampled parameter estimates along with the patient-specific observed covariate 
values, observed exacerbation counts, and length of unobserved interval will be 
used in conjunction with a random number generator to impute an event count for 
the unobserved time period, which is added to the observed event count 
(Keene et al. 2014). These augmented datasets will be analyzed according to the 
model described in Section 4.5.1 and the results combined using Rubin’s rules.

In the tipping point sensitivity analysis, the underlying event rate used to impute 
unobserved event counts for a given arm will be adjusted via a multiplier delta; a 
separate delta will be applied to each arm.  A range of delta values will be used to 
adjust the underlying event rate used for imputation in the MSTT1041A and placebo 
arms independently based on a grid of delta adjustments.  The delta values will be 
chosen on the basis of the treatment effect (rate ratio) observed for a given 
MSTT1041A arm compared with placebo from the analyses described in 
Section 4.5.1.  The range of delta values will include cases where dropouts from the 
MSTT1041A arm are assumed to have worse outcomes than dropouts from the 
placebo arm.  For each endpoint, the resulting point estimates of treatment effect 
and corresponding p-values under each pair of deltas for each MSTT1041A and 
placebo comparison will be tabulated.
Also, for the secondary endpoint (absolute change from baseline in FEV1), a cumulative 
responder plot which displays, by treatment arm, the proportion of patients who achieve 
each specified absolute change in pre-bronchodilator FEV1 from baseline at Week 54 for 
a range of possible FEV1 changes will be provided.  For this plot, patients with missing 
Week 54 data will be assumed to be non-responders.
4.5.5
Subgroup Analyses
Exploratory subgroup analyses of the primary efficacy endpoint will be performed to 
evaluate the consistency of the primary analysis results across pre-specified subgroups 
defined by demographic and baseline characteristics.  The following subgroups will be 
analyzed with respect to the primary efficacy endpoint (incidence of asthma 
exacerbations) and for the secondary efficacy endpoint (absolute change in 
pre-bronchodilator FEV1 from randomization at Week 54):

Age (18 to50 years, 50 to65 years,65 years)

Sex (male, female)

Baseline ICS total daily dose (1000 µg,1000 µg of fluticasone propionate or 
equivalent)

Number of asthma exacerbations in the 12 months prior to study entry (1 event, 
2 events,3 events)

Geographic region (North America, Latin America, Eastern Europe, Western Europe 
plus Rest of World)


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Biomarker subgroup analyses are specified in Section 4.5.6.
A Poisson regression model similar to that specified for the primary analysis 
(Section 4.5.1) will be used for each subgroup analysis based on data subset for the 
patient subgroup of interest.  Baseline covariates included in the primary analysis but no 
longer relevant given the subgroup of interest will be excluded from the model.  A similar 
approach will be used for the secondary efficacy endpoint based on FEV1.  If 
convergence problems with the statistical models arise due to a small number of patients 
per subgroup, the analysis may be simplified by combining some of the subgroups or by 
excluding baseline stratification variables from the model.  The estimated treatment 
effects (MSTT1041A vs. placebo) and corresponding 95% CIs from the models will be 
displayed graphically for each MSTT1041A dose level and each level of the subgroups 
specified.
4.5.6
Biomarker Analyses
Additional biomarker analyses will be performed to further evaluate the treatment benefit 
by biomarker-defined patient subpopulations.  Two biomarkers will be considered 
individually: blood eosinophils and IL1RL1 genotype.
Based on the primary efficacy endpoint (incidence of asthma exacerbations) and the  
secondary efficacy endpoint (absolute change in pre-bronchodilator FEV1 from the 
randomization visit at Week 54), the treatment benefit will be assessed for the following 
pre-specified biomarker-defined patient subpopulations:

Blood eosinophil level at visit 1:  Eosinophil-high will be defined as 300 cells/µL
and eosinophil-low will be defined as300 cells/ µL at visit 1.  It is estimated that 
approximately 25% of enrolled patients will be classified as eosinophil-high.

IL1RL1 genotype:  Patient subsets will be defined by IL1RL1 genotype, using the 
Single Nucleotide Polymorphisms (SNP) at rs10206753. Genotype-positive will be 
defined as those patients who are homozygous for the common variant (i.e., TT).  
Genotype-negative will be defined as patients who are not homozygous for the 
common variant (i.e., CT or CC). It is estimated that approximately 50% of enrolled 
patients will be classified as genotype-positive.
For the primary efficacy endpoint, a Poisson regression model similar to that specified 
for the primary analysis (Section 4.5.1) will be used for each subgroup analysis based on 
data subset for the biomarker subgroup of interest.  Baseline covariates included in the 
primary analysis but no longer relevant given the subgroup of interest will be excluded 
from the model.  A similar approach will be used for the secondary efficacy endpoint 
based on FEV1. Point estimates for the treatment benefit (MSTT1041A vs. placebo) 
within each biomarker patient group as defined above will be presented along with 95% 
CIs and p-values.
Similarly, the appropriateness of the chosen cutoff values to define the 
biomarker-high/genotype-positive versus biomarker-low/genotype-negative patient group 


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for the primary analysis (e.g., 300 cells/ µL for eosinophils) will be assessed by 
performing additional analyses for the primary efficacy endpoint (incidence of asthma 
exacerbations) and the secondary efficacy endpoint (absolute change in 
pre-bronchodilator FEV1 from randomization at Week 54) with the use of pre-specified 
alternative subgroups:

Alternative Subgroups for Blood Eosinophils:  Patients will be categorized into 
blood eosinophil subgroups defined as150 cells/ µL and150 cells/ µL at visit 1.

Alternative Subgroups for IL1RL1 Genotype:  Patients will be categorized into 
one of three genotype subgroups: TT, CT, or CC.
Covariate adjustment for these analyses will follow the principles as described in 
Section 4.5.  All other elements of the analysis will remain the same as in the primary 
analysis.  If convergence problems with the statistical models arise due to a small 
number of patients per subgroup, the analysis may be simplified by excluding baseline 
stratification variables from the model.  Point estimates for the treatment benefit 
(MSTT1041A vs. placebo) within each biomarker patient subgroup will be presented as 
defined above, along with associated 95% CIs and p-values.
Additional exploratory analyses that will be performed include: 

Prognostic Effect:  The prognostic effect of blood eosinophils and IL1RL1
genotype will be evaluated by assessing the relationship between baseline 
biomarker levels and the observed rate of protocol-defined exacerbations based on 
patients who received treatment with placebo.

Treatment by Biomarker Interaction:  This study was not designed to compare 
the reduction in asthma exacerbation rate associated with MSTT1041A treatment 
between the biomarker-high/genotype-positive and the biomarker-low/ 
genotype-negative patient groups.  However, a comparison of the treatment by 
biomarker interaction for each of the individual biomarkers (as categorized above) 
will still be performed. In addition, the interaction of treatment by eosinophil level, 
treated as a continuous variable, will be explored.

Association between Blood Eosinophils and IL1RL1 Genotype:  The 
relationship between blood eosinophils and IL1RL1 genotype will be evaluated 
graphically by displaying blood eosinophil level at visit 1 by genotype.

Relationship with Demographics and Disease Characteristics:  The relationship 
between each biomarker (blood eosinophils and IL1RL1 genotype) and 
demographics and disease characteristics (including but not limited to age, sex, 
race, geographic region, and the number of asthma exacerbations in the 12 months 
prior to study entry) will be evaluated.
4.6
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Several candidate PD biomarkers have been identified (e.g., FeNO, blood eosinophils, 
serum sST2, serum IL-5, plasma LIGHT, and serum amphiregulin) and will be measured 
to assess the effect of MSTT1041A on these biomarkers.  Descriptive summaries of the 


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PD biomarker values at each visit, as well as changes from the randomization visit
(absolute or percent change as appropriate), will be summarized by treatment arm.
The analyses of all PD endpoints will be based on the safety-evaluable population 
(see Section 4.1.2).
Serum MSTT1041A concentrations are measured at the following timepoints during the 
double-blind treatment period:  Weeks 2, 6, 10, 14, 26, 38, 50, 54, and 70 (Predose, 
Cmin,Wk4, Cmin,Wk8, Cmin,Wk12, Cmin,Wk24, Cmin,Wk36, Cmin,Wk48, Cmin,Wk52, follow-up concentration).  
The difference in the weeks for the concentration and the visit week is due to fact that 
study drug is given on Week 2 of the study, which is the start of the double-blind 
treatment period. In a subset of patients (approximately 20 per group), additional PK 
samples will be collected following first dose and at Week 26 for characterization of 
absorption and accumulation of MSTT1041A following SC administration.  These 
concentrations will be tabulated and summarized using descriptive statistics (mean, 
standard deviation, coefficient of variation, median, minimum, and maximum) by 
treatment group and timepoint based on the safety-evaluable population (see 
Section 4.1.2).  While treatment groups will be defined according to the actual treatment 
received, a review of dosing information including dosing errors, if any, and of the PK
data for patients with unusual dosing patterns will be conducted to assess for any 
potential impact on the results.
Additional PK analyses of the double-blind treatment period data may be conducted as 
appropriate.  Population PK modeling may be performed to characterize inter-individual 
variability, which may be reported separately from the clinical study report.  Exploratory 
exposure-response analyses will be performed as appropriate, and may be reported 
separately from the clinical study report.
4.7
SAFETY ANALYSES
Safety will be assessed through the summary of adverse events, serious adverse events, 
adverse events of special interest, laboratory test results (hematology and serum 
chemistry, urinalysis), incidence of antibodies against MSTT1041A, ECG findings, and 
vital signs.  Safety summaries for the 52-week double-blind treatment period will include 
outcomes as described in Section 2.1.4.  This may include data collected at 
unscheduled visits, early termination visits, or safety follow-up visits.
Safety outcomes will be summarized based on the safety-evaluable population with
patients grouped according to the actual treatment received (see Section 4.1.2).  Safety 
summaries will be presented by treatment arm for all treated patients.
Safety assessments will also be conducted on the run-in safety-evaluable population, 
which consists of all patients who receive a placebo dose during the run-in period 
regardless of whether or not the patient is randomly allocated into the double-blind 
treatment period (see Section 4.1.3).  These safety analyses will consider adverse 


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events that occur during the 2week run-in period.  Events that occur during this period 
will be followed until resolved.
4.7.1
Exposure to Study Medication
Exposure to study drug (number of study drug administrations and duration of treatment) 
will be summarized for the 52week double-blind treatment period by treatment arm.  
Duration of treatment will be defined based on the difference (in days) between the 
dates of the first and last dose of study drug during the 52week double-blind treatment 
period (Week 2 to Week 50 treatments) plus 29 days.
A listing of study drug administration with information on dosing errors during the 
placebo run-in and double-blind treatment periods will be provided.
4.7.2
Adverse Events 
Verbatim descriptions of treatment-emergent adverse events will be coded using the 
latest version of MedDRA.  A treatment-emergent adverse event is defined as any new 
adverse event or any worsening of an existing condition with an onset date on or after 
the first study drug administration date.  Summaries of treatment-emergent events will 
be provided for each of the following categories:

All adverse events

All adverse events by most extreme severity

Adverse events assessed as related to study treatment by the investigator

All serious adverse events

All suspected unexpected serious adverse events

Adverse events that are a result of an error in study drug administration

Adverse events leading to discontinuation of study treatment

Adverse events leading to study discontinuation

Adverse events of special interest
The adverse events of special interest will be identified as follows.  Summaries will 
include tabulations by Medical Dictionary for Regulatory Activities (MedDRA) terms and 
listings, as appropriate.

Cases of potential drug-induced liver injury that include an elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with 
either an elevated bilirubin or clinical jaundice, as defined by Hy’s law.

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 


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a patient exposed to a medicinal product.  This term applies only when a 
contamination of the study drug is suspected.

Potential major adverse cardiac events (MACE) will be identified as follows.
Death due to cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke 
or transient ischemic attack (TIA), unstable angina or chest pain requiring 
hospitalization, coronary revascularization, and congestive heart failure (CHF) 
requiring hospitalization.
In addition, patient deaths and the primary cause of death will be listed, as well as any 
cases of pregnancy, anaphylaxis, anaphylactoid, and hypersensitivity.
4.7.3
Laboratory Data
Descriptive summaries of laboratory values at screening, run-in, randomization, and 
during the 52week double-blind treatment period, including changes from the 
randomization visit, will be generated for hematology, chemistry, and urinalysis
parameters. The proportion of patients with values outside the normal upper and lower 
limit at each visit will be calculated overall and by change from the randomization visit.  
In addition, selected lab parameters (including, but not limited to, AST, ALT, alkaline 
phosphatase, total bilirubin, hemoglobin, and absolute neutrophil count ) will be 
summarized by grade using the WHO grading scale (2003).
The number and percentage of patients with positive serum antibodies against 
MSTT1041A at baseline and during the 52week double-blind treatment period will be 
tabulated. The relationship between ADA status and safety, efficacy, PK, and biomarker 
endpoints will be explored. 
4.7.4
ECG Results
The number and percentage of patients with abnormal ECG findings at screening, run-in 
(Week 0), randomization (Week 2), Week 4, Week 26, and Week 54 will be summarized.
In addition to the primary investigator, a separate agency (Cardiocore through 
Vitalograph) will review all ECG’s independently.  ECG findings that change from normal 
to abnormal or an abnormality to a different abnormality will be analyzed and 
summarized.
For corrected QT interval using Fridericia’s method (QTcF), PR, and QRS intervals as 
well as heart rate, the values at each timepoint as well as changes from randomization
will be summarized descriptively.  The difference in mean QTcF change from 
randomization between each MSTT1041A arm and placebo and the corresponding 
2-sided 90% CI will be summarized for Week 26 and Week 54.
The proportion of patients who experience a QTcF value450,480, or500 ms for 
males or470,490, or510 ms for females at a given visit, or an increase from 
randomization in QTcF of30 and60 ms will be summarized.  The proportion of 


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patients who experience a QTcF value450 ms for males or470 ms for females, or a 
QTcF increase from baseline of30 ms at any time during the study will be summarized.
In the event that a patient has more than three valid ECG records per visit, only the last 
three readings (by timestamp) will be analyzed.  For example, if a patient has four valid 
ECG records for the screening visit, only readings two through four will be analyzed, and 
the first reading will be ignored.
4.7.5
Vital Signs
Descriptive summaries of vital sign measurements and changes from randomization will 
be generated.
For the vital sign parameters of heart rate, respiration rate, systolic blood pressure, and 
diastolic blood pressure, the proportion of patients with a high or low value based on the 
cutoffs specified in Table 2 and the proportion of patients with a change from baseline 
(increase or decrease) of the amount specified in Table 2 will be summarized by visit.
Table 2
Cutoff Values for Summary of Vital Signs
Value at Visit
Change from Baseline
Vital Sign
Units
Low
High
Decrease
Increase
Heart rate
beats/min
55
100
20
20
Respiration rate
breaths/min

17
10
10
Systolic blood pressure
mmHg
90
140
20
20
Diastolic blood pressure
mmHg

90
15
15
4.8
MISSING DATA
Missing efficacy data will not be imputed for the primary efficacy endpoint (incidence of 
asthma exacerbations) or for the secondary efficacy endpoint absolute change in 
pre-bronchodilator FEV1 from randomization visit at Week 54.  Instead, missing data will 
be accounted for in the model as described in Section 4.5.1 and Section 4.5.2.  Analyses 
to explore the sensitivity of results to missing data assumptions will be conducted as 
described in Section 4.5.4.
Missing data for other secondary and exploratory endpoints will be handled as described 
in Sections 4.5.2 and 4.5.3.
4.9
INTERIM ANALYSES
No efficacy interim analyses are planned or were conducted.


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5.
REFERENCES
Barnard J and Rubin DB. Small-sample degrees of freedom with multiple imputation.
Biometrika 1999; 86:94855.
Keene ON, Roger JH, Hartley BF, et al. Missing data sensitivity analysis for recurrent 
event data using controlled imputation. Pharmaceut Statist 2014;13:25864.
WHO Toxicity Grading Scale For Determining The Severity Of Adverse Events. 
[Accessed 8 May 2017]. Available from 
http://www.icssc.org/Documents/Resources/AEManual2003AppendicesFebruary_
06_2003%20final.pdf