A Phase 3, Multicenter, Randomized, Double-blind Study of a Single Dose of S-033188 Compared With Placebo or Oseltamivir 75 mg Twice Daily for 5 Days in Patients With Influenza at High Risk of Influenza Complications
Phase: PHASE3
Conditions: Influenza
Sponsor: Shionogi

 
Shionogi Study Title:  
A Phase 3, Multicenter, Randomized, Double-blind 
Study of a Single Dose of S-033188 Compared with 
Placebo or Oseltamivir 75 mg Twice Daily for 5 Days in 
Patients with Influenza at High Risk of Influenza 
Complications 
Shionogi Study Number: 
1602T0832 
ClinicalTrials.gov 
Registration No. 
NCT02949011  
Study Document 
Protocol Version 3 (Amendment 2) 
 
History of Protocol Amendments 
Version 1 (Original) 
05 August 2016 
This version of the protocol was not used to conduct the study 
Version 2 
16 September 2016 
This version of the protocol was not used to conduct the study 
Version 3 
31 October 2016 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
  
 
 
   
 
  
   
   
   
  
   
   
   
  
   
    
  
               
  
  
   
     
  
    
    
  
    
       
 
  
     
    
 
    
    
  
 
  
 
  
      
  
  
    
  
  
 
    
    
   
    
  
 
      
      
    
        
   
  
         
  
  
    
 
  
      
  
          
    
     
  
  
      
  
    
     
 
  
    
  
    
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
 
  
 
 
   
  
  
  
    
     
 
    
    
      
  
        
   
        
 
 
  
 
 
  
  
  
  
 
    
    
     
       
  
    
 
  
       
   
  
   
   
 
  
  
 
    
    
     
       
  
   
      
    
         
      
   
  
   
    
 
    
    
     
       
  
    
 
  
    
  
   
    
 
    
    
     
       
  
   
               
    
  
  
    
 
  
  
 
    
    
   
  
    
  
  
  
  
          
   
   
    
  
 
    
    
    
    
     
    
  
    
    
    
    
     
   
             
    
    
   
  
   
    
    
 
   
    
                 
 
  
 
    
   
     
     
    
 
  
    
    
 
  
  
  
  
 
    
      
  
    
     
 
       
  
  
  
  
     
  
    
            
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
  
 
    
  
  
 
  
   
  
  
 
    
  
    
 
  
         
   
       
  
 
             
  
    
        
    
 
      
    
    
        
    
      
      
  
    
  
       
  
  
  
 
    
    
    
    
   
 
  
  
  
  
 
  
   
  
     
     
     
     
 
     
      
  
  
  
  
  
 
     
      
  
  
  
  
  
 
  
 
  
  
  
  
 
       
  
     
     
     
     
 
  
 
      
  
  
  
  
  
 
  
 
      
  
  
  
  
  
 
 
  
  
  
  
 
  
   
  
     
     
     
     
 
  
 
      
  
  
  
  
  
 
  
 
      
  
  
  
  
  
 
           
   
   
            
  
  
   
    
      
       
 
  
 
   
  
            
   
   
      
  
  
  
  
    
   
    
   
       
    
    
  
    
  
  
  
 
   
  
  
  
    
    
 
 
 
    
        
  
      
     
 
  
        
    
  
  
  
  
     
     
  
    
  
  
 
   
  
  
    
   
   
  
    
    
      
  
              
    
 
  
  
  
     
   
  
  
         
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
  
      
  
    
  
      
   
   
       
 
            
  
    
  
  
 
  
  
        
    
        
     
  
   
     
   
  
 
  
  
  
  
    
  
       
  
 
  
  
  
    
     
 
      
  
       
      
  
 
     
          
   
   
 
  
        
     
    
         
    
 
  
  
    
  
        
    
 
 
     
   
  
  
      
  
  
  
     
           
   
   
  
    
  
 
  
  
      
     
   
  
      
          
  
  
 
  
    
    
  
   
  
  
 
    
  
 
  
  
  
  
  
 
  
   
    
    
  
 
  
  
  
  
  
  
 
 
  
       
    
    
  
  
 
  
 
    
  
       
 
    
  
       
 
 
   
  
  
  
    
  
    
  
    
    
  
  
 
  
  
  
  
    
    
 
  
  
  
   
    
  
    
   
  
  
  
  
  
     
  
 
  
         
  
  
    
  
 
  
  
  
   
    
  
  
  
     
  
  
    
 
 
  
  
  
    
     
  
      
   
  
        
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
   
       
      
  
  
 
 
         
  
      
      
 
  
    
  
    
  
  
  
  
  
    
  
   
  
  
 
  
   
  
    
  
  
      
  
  
  
  
  
       
  
        
    
    
        
  
  
  
  
      
  
       
  
      
  
    
  
  
     
  
      
         
   
       
 
 
 
  
  
   
   
  
  
   
          
    
  
   
  
      
  
    
  
 
 
    
 
  
    
  
     
  
  
  
 
  
  
  
      
  
    
  
  
  
    
  
         
  
    
  
  
    
    
    
    
       
 
   
        
  
 
   
  
  
      
  
  
  
  
       
    
     
  
 
  
  
      
  
  
  
  
 
  
    
  
           
 
  
  
      
   
  
  
      
         
  
    
  
  
     
      
   
  
  
       
     
  
    
   
   
  
  
 
    
  
  
  
    
  
 
  
   
    
  
   
   
        
        
    
   
         
        
     
    
  
         
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
  
    
  
    
  
 
 
   
    
   
   
         
      
   
   
  
     
        
    
   
  
     
        
  
  
   
    
  
   
   
  
    
        
     
   
  
     
        
     
    
  
         
   
 
    
  
  
 
       
  
   
  
    
  
  
      
                        
 
  
  
  
  
  
  
      
    
    
  
    
  
  
 
 
    
  
 
 
  
  
 
  
  
    
 
  
    
 
 
  
  
  
   
  
  
    
   
    
 
  
 
  
 
   
      
   
   
  
     
  
       
   
  
      
    
                
   
  
  
      
   
  
  
      
 
  
 
 
 
  
  
  
           
   
  
 
  
    
  
  
  
 
 
   
  
          
   
  
   
        
 
    
            
     
    
 
 
 
  
    
            
      
 
 
   
     
            
 
 
   
  
  
      
        
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
 
   
    
  
    
  
    
 
   
  
          
 
 
   
      
  
  
 
 
 
    
 
 
   
      
  
  
    
 
 
  
 
 
   
    
 
   
  
  
  
        
 
  
        
 
   
     
  
 
 
   
   
  
  
 
 
    
  
    
  
   
 
 
 
  
  
 
  
  
 
 
  
    
  
  
 
 
  
      
   
 
 
 
  
  
   
 
   
  
    
        
 
  
   
    
   
 
  
  
 
  
 
 
  
 
  
 
   
  
  
  
       
  
 
 
  
    
  
   
  
 
    
   
  
 
  
  
      
 
  
               
  
  
        
 
      
  
           
              
  
 
 
  
  
  
   
  
    
     
    
  
  
  
     
    
    
   
     
    
  
    
  
  
      
 
    
  
        
  
  
  
  
  
 
  
  
  
      
      
  
      
   
  
    
  
    
     
  
  
      
  
  
   
 
    
  
   
    
   
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
    
  
      
      
  
     
 
   
   
        
  
     
      
           
    
  
  
  
  
    
  
 
  
   
  
  
      
      
    
  
    
  
  
    
  
     
  
         
  
  
  
      
 
  
    
      
    
  
     
  
   
     
    
  
   
         
      
  
  
   
  
 
  
  
  
 
  
  
  
      
     
  
  
 
  
  
  
    
    
  
   
   
      
  
    
  
 
     
      
   
    
   
        
      
  
    
  
    
   
        
    
  
 
    
        
  
  
  
  
   
  
  
  
  
  
 
  
    
    
             
   
  
  
       
  
    
  
   
      
     
             
  
  
  
  
   
  
     
  
  
      
 
 
   
    
   
   
 
    
    
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
 
 
  
    
 
  
    
  
 
  
    
  
 
  
   
  
 
    
 
  
 
 
  
 
  
 
  
 
 
  
 
 
  
 
  
 
  
 
  
 
    
  
  
 
  
 
 
    
  
  
  
  
   
 
  
  
  
  
  
  
    
 
  
  
    
  
  
    
 
  
  
  
 
  
 
  
    
  
 
 
 
  
 
   
  
 
  
  
    
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
    
  
 
  
 
 
 
  
 
  
  
 
  
 
  
  
 
  
 
  
  
 
  
 
  
 
  
 
  
 
  
 
  
  
  
  
 
  
 
  
 
  
 
  
  
     
  
 
    
  
    
    
  
  
  
 
  
  
 
  
 
  
       
 
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
  
 
  
 
  
   
  
 
  
 
  
  
      
 
  
 
  
  
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
 
 
  
 
   
 
  
 
   
  
 
 
  
 
  
 
  
 
     
 
  
 
    
          
 
  
 
   
  
   
  
 
 
 
 
 
 
 
 
    
 
  
 
   
 
  
 
  
  
   
   
  
 
  
 
  
 
 
 
 
 
  
 
  
 
  
  
    
 
  
 
  
  
 
  
 
  
 
  
 
  
 
  
 
  
 
 
  
 
 
  
  
   
 
  
 
  
 
  
 
  
  
    
  
 
  
 
  
  
    
 
  
 
 
 
 
 
     
    
  
   
  
 
  
 
  
 
  
  
 
  
 
  
  
 
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
   
   
  
 
  
 
   
 
  
 
 
  
 
   
  
 
  
   
  
 
  
 
  
 
  
 
  
 
  
 
  
 
   
 
  
 
 
  
 
  
 
  
 
  
 
  
 
  
   
  
 
   
  
 
    
  
 
  
  
    
 
  
 
  
  
 
  
 
  
  
  
 
  
 
 
  
 
 
  
 
 
 
 
 
 
  
 
  
  
   
  
    
 
 
 
  
 
  
  
 
  
 
  
  
 
  
 
  
   
  
  
   
 
 
 
 
 
 
  
 
  
 
  
 
  
  
     
  
 
   
  
    
    
 
  
  
      
 
  
 
  
  
 
  
 
 
  
 
  
  
 
 
 
 
    
      
    
  
 
 
 
 
  
      
 
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
  
 
  
 
  
  
 
  
 
  
  
 
  
 
 
  
 
  
 
  
 
   
 
  
 
    
 
  
 
  
 
  
 
  
     
   
  
 
 
  
 
  
 
 
 
  
 
   
   
  
 
  
 
  
 
   
   
  
 
  
 
  
 
    
 
 
  
 
   
    
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
  
  
 
  
 
  
  
 
  
 
   
  
 
  
 
   
 
  
 
   
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
  
 
  
 
 
  
 
  
 
  
 
  
 
  
 
  
  
   
  
 
   
  
    
  
    
  
 
  
  
      
 
  
 
  
  
 
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
  
 
 
 
   
 
  
 
 
  
   
  
  
   
 
 
 
 
 
  
   
    
  
  
   
  
 
  
 
 
  
   
    
  
  
 
 
 
 
 
  
 
  
 
 
  
   
  
 
 
    
      
   
 
 
 
  
 
 
    
    
  
  
   
 
   
   
  
  
 
 
  
   
  
  
   
 
 
 
 
    
  
 
 
 
  
 
  
 
 
     
   
  
   
 
   
          
    
  
 
  
       
   
 
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
 
    
 
  
  
    
     
  
 
 
  
 
 
 
 
 
 
 
  
   
 
 
  
  
 
 
 
 
  
    
 
  
 
   
  
    
 
  
  
     
   
  
   
  
    
 
  
         
       
  
    
  
 
 
 
  
  
  
  
 
 
  
 
 
 
    
 
 
       
 
 
    
 
 
  
    
  
 
 
   
  
    
  
 
  
 
 
  
 
 
  
  
 
  
  
  
  
 
 
  
 
 
  
  
 
 
  
 
 
 
    
 
 
    
  
  
  
  
 
 
 
  
    
   
 
   
 
 
  
  
 
 
 
 
 
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
     
 
 
  
 
 
  
      
             
  
  
 
 
  
 
 
  
  
 
 
 
  
 
 
 
  
 
 
  
    
  
   
 
 
  
  
  
   
   
 
  
  
  
 
 
 
   
  
  
  
   
  
  
 
 
  
  
 
 
      
 
  
   
 
  
  
 
 
  
  
  
 
 
 
  
  
 
  
 
 
  
 
  
    
  
  
 
 
  
 
  
   
  
      
  
 
  
  
  
 
  
  
    
  
 
 
    
 
   
  
  
 
 
 
 
  
 
   
  
  
  
   
  
  
  
 
  
  
  
  
 
 
  
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
 
 
 
 
 
 
  
 
   
  
  
  
          
  
 
  
  
  
    
  
  
  
  
  
  
 
  
    
 
  
  
 
 
  
   
 
  
 
  
    
 
 
  
  
  
  
  
 
 
  
  
  
 
 
 
  
  
  
   
  
  
  
  
 
 
 
 
     
 
 
  
 
 
  
  
 
  
  
    
 
   
  
  
    
 
  
   
  
 
 
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
 
       
  
  
      
  
  
  
 
  
  
  
    
     
    
  
     
  
  
  
  
       
 
           
      
  
     
 
     
    
           
  
  
  
   
      
  
     
         
  
 
    
  
   
  
  
      
   
       
  
         
 
   
         
   
       
  
   
  
    
  
         
       
 
  
  
   
  
  
  
  
   
      
    
 
  
  
    
    
  
    
 
        
  
  
      
  
 
     
    
  
  
  
   
  
  
     
  
   
    
  
    
    
  
    
  
    
 
       
      
    
    
   
           
   
  
     
      
 
  
    
  
    
          
    
  
   
    
    
   
  
  
 
    
   
  
    
  
    
      
   
    
  
        
       
   
    
  
     
  
      
    
 
  
        
  
  
  
     
     
         
            
   
   
  
  
    
    
  
     
    
        
        
  
  
      
  
        
  
      
 
    
  
    
    
     
  
 
  
  
  
  
  
  
  
 
  
        
 
    
  
  
  
   
    
  
  
  
     
   
    
      
  
        
    
 
    
  
  
  
    
   
  
  
  
    
      
    
     
   
    
     
  
    
       
  
   
  
   
  
        
    
  
    
  
   
    
     
         
  
   
   
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
  
 
  
  
  
    
 
 
  
 
  
   
  
  
      
  
 
  
     
  
   
       
             
       
  
   
  
   
  
  
     
   
 
    
  
  
  
  
    
 
     
  
   
    
    
  
 
  
 
  
  
    
   
  
    
    
  
    
   
   
  
  
    
  
  
 
  
   
        
        
   
   
   
  
   
   
    
  
        
    
   
  
   
  
      
  
  
  
  
        
     
  
  
  
    
   
  
  
 
  
 
  
  
  
      
  
 
   
   
    
  
   
    
  
 
   
    
  
      
        
 
  
    
  
      
  
  
    
    
   
   
      
  
  
  
  
 
      
      
   
  
  
  
 
    
    
    
  
         
     
   
   
    
        
  
  
 
      
  
  
  
  
    
 
  
     
  
    
     
  
    
 
        
     
  
    
        
  
 
    
  
  
        
      
   
  
     
   
            
   
  
  
  
        
  
    
     
  
    
  
  
  
  
 
  
  
  
    
  
  
 
 
      
  
 
  
   
 
  
  
    
     
  
    
    
 
  
  
  
    
  
  
  
  
 
  
    
  
    
  
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
  
  
  
 
  
 
 
  
    
  
  
  
  
 
  
  
     
  
  
  
 
  
  
  
      
    
  
  
 
  
 
 
  
  
 
  
  
  
  
  
 
  
 
  
  
  
  
 
  
   
  
    
    
 
  
  
    
  
     
      
     
 
 
  
  
  
  
  
  
      
   
           
  
      
       
 
       
  
  
    
   
   
  
  
    
  
  
  
 
  
    
  
  
    
  
  
 
  
     
  
  
  
    
  
  
    
  
  
  
  
    
 
   
  
    
  
  
  
   
        
    
  
       
    
  
    
    
 
  
 
  
         
  
   
   
 
                      
          
                     
  
       
  
  
    
  
 
         
    
     
  
 
      
      
    
      
   
   
  
   
    
      
    
            
 
    
    
  
  
  
    
  
  
   
  
  
  
  
   
  
 
  
    
          
  
  
   
    
 
  
  
  
 
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
 
 
   
  
  
 
  
  
     
   
 
  
    
     
       
  
    
 
  
       
   
  
   
   
 
 
  
  
  
 
  
  
     
   
 
  
    
     
       
  
   
               
       
  
  
   
    
 
    
    
     
       
  
    
 
  
    
  
   
    
 
    
    
     
       
  
   
               
    
  
  
    
 
 
   
  
  
 
    
  
     
   
   
    
   
  
    
  
  
  
  
          
   
   
   
 
  
  
 
    
    
    
    
     
    
  
 
  
    
    
    
     
   
             
    
    
   
  
   
    
    
 
   
    
                 
 
 
 
  
 
    
     
   
 
  
         
     
    
   
 
  
    
 
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
  
  
  
 
    
      
  
    
   
       
   
   
  
     
  
    
 
             
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
  
  
  
   
  
  
     
 
   
  
  
  
   
    
    
    
     
      
  
 
  
     
  
       
  
  
   
     
  
   
  
  
     
  
  
   
       
  
             
    
     
    
  
  
      
    
  
     
   
     
  
  
   
    
  
    
        
 
   
  
    
  
  
 
  
  
    
  
  
  
       
 
       
    
    
         
 
    
  
    
  
    
  
  
  
  
        
  
    
        
     
  
    
   
      
     
    
  
   
      
  
      
   
  
  
  
   
   
    
 
      
    
    
       
      
 
  
   
        
  
    
 
  
  
      
     
   
    
   
   
  
     
   
  
     
    
    
  
  
      
       
 
 
  
      
       
      
   
  
  
     
       
    
 
  
     
  
   
  
   
  
     
      
    
  
  
      
  
    
  
  
    
    
  
    
  
  
  
  
     
  
  
    
  
  
  
      
   
        
  
  
    
   
  
  
  
   
   
  
            
 
  
      
     
          
 
    
    
          
   
 
    
  
    
   
  
      
   
    
  
  
  
       
  
      
 
   
  
    
  
    
   
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
 
 
 
  
  
 
          
  
    
         
  
     
  
           
  
 
    
  
    
  
   
  
   
      
     
       
  
  
    
      
  
        
 
    
    
       
    
    
 
  
      
  
  
  
 
    
        
  
      
     
 
 
        
    
  
  
  
  
     
     
  
    
  
  
 
   
  
  
    
   
   
  
    
    
      
  
              
    
 
  
  
  
     
   
  
  
         
 
  
      
  
    
  
    
     
 
   
    
 
            
  
    
  
  
 
  
  
        
    
        
     
  
   
     
   
  
 
  
  
  
  
    
  
       
  
 
  
  
  
    
     
 
      
  
       
      
  
 
     
          
   
   
 
  
        
     
    
         
    
 
  
  
    
  
        
    
 
 
     
   
  
  
  
      
  
 
   
     
           
  
    
  
    
  
 
  
  
      
     
   
  
      
          
  
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
    
  
   
  
  
 
 
    
  
 
  
  
  
  
  
 
  
   
    
    
  
 
  
  
  
  
  
  
 
 
  
       
    
    
  
  
 
  
 
    
  
       
    
  
       
 
 
   
  
  
  
    
  
    
  
    
    
  
  
 
  
  
  
  
    
    
 
  
  
  
   
    
  
    
   
  
  
  
  
  
     
  
 
  
          
  
  
    
  
 
  
  
  
   
    
  
  
  
     
  
  
    
 
 
  
  
  
    
  
     
  
      
   
  
        
 
   
       
    
    
  
    
  
  
  
 
 
  
 
           
  
      
      
 
 
    
  
    
  
  
  
  
  
    
  
   
  
  
  
   
  
    
  
  
      
  
  
  
  
  
       
  
        
    
    
        
  
  
  
  
      
  
       
  
      
  
    
  
  
     
  
      
         
   
       
 
 
 
  
  
   
   
  
  
   
          
    
  
   
  
      
  
    
  
 
   
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
  
     
  
  
  
 
 
  
  
      
  
    
  
  
  
    
  
         
  
    
 
  
    
    
    
    
       
 
   
        
  
 
   
  
  
      
  
  
  
  
       
    
     
  
 
  
  
      
  
  
  
  
 
  
    
  
           
 
  
  
      
   
  
  
      
         
  
    
        
      
   
  
  
       
     
  
    
   
   
  
  
 
    
  
 
  
  
 
  
    
   
    
   
     
     
 
 
    
    
  
     
  
    
  
    
  
 
    
  
  
  
    
  
 
   
  
  
         
  
      
      
  
  
    
    
  
      
    
   
        
    
     
  
    
  
  
 
      
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
 
 
 
    
 
  
  
 
 
  
  
  
     
 
  
  
 
  
        
  
    
       
 
  
 
  
  
  
  
     
 
  
 
  
  
    
  
  
    
  
   
 
  
  
  
  
  
    
  
  
 
 
  
  
 
  
  
  
  
  
  
  
  
 
 
  
     
 
      
          
  
        
     
  
  
   
     
  
 
    
  
   
   
   
  
   
    
          
  
  
   
  
     
  
    
  
  
    
         
  
  
    
      
         
  
     
     
          
    
  
 
       
  
  
       
      
       
    
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
  
 
 
  
 
    
    
    
    
   
 
  
  
  
  
 
  
   
  
     
     
     
     
 
  
 
      
  
  
  
  
  
 
     
      
  
  
  
  
  
 
  
 
  
  
  
  
 
       
  
     
     
     
     
 
  
 
      
  
  
  
  
  
 
  
 
      
  
  
  
  
  
 
 
  
  
  
  
 
  
   
  
     
     
     
     
 
  
 
      
  
  
  
  
  
 
  
 
      
  
  
  
  
  
 
           
   
   
            
  
  
   
    
      
       
 
   
    
    
    
  
 
      
  
      
  
      
  
 
   
            
    
  
        
  
  
   
      
    
        
    
        
    
       
    
 
  
         
    
       
 
   
    
  
    
  
 
  
     
         
      
   
 
   
       
    
    
  
  
 
       
  
   
    
  
    
    
 
   
        
 
  
    
 
  
   
  
  
           
    
 
  
      
          
  
  
  
   
      
     
    
    
      
    
  
   
  
  
  
  
 
  
 
    
               
  
  
    
 
  
   
 
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
 
  
      
    
 
  
    
  
 
 
    
   
  
    
    
 
        
  
 
    
    
  
   
    
  
   
  
    
   
   
  
  
  
    
        
  
      
    
    
    
  
     
      
     
  
  
    
   
 
  
        
          
   
 
  
  
      
  
    
  
  
 
  
      
  
        
  
  
 
      
  
  
  
  
  
  
  
      
  
    
     
  
  
       
     
 
     
     
  
       
    
   
 
  
  
   
    
  
   
      
  
 
  
  
      
  
     
  
  
    
    
   
  
        
  
   
       
  
     
  
     
   
     
  
    
      
    
   
    
      
  
  
    
  
    
  
    
    
    
  
       
    
          
  
    
    
    
 
  
      
    
     
      
 
    
  
    
  
      
    
 
  
  
  
  
  
  
     
     
     
  
  
  
  
   
    
    
  
      
   
     
        
   
  
   
    
 
  
  
      
   
    
   
  
 
 
      
  
  
      
  
     
  
     
    
        
      
 
  
  
  
  
      
  
    
  
     
  
  
     
    
       
      
     
          
     
  
   
            
            
    
  
   
  
  
   
      
 
  
  
   
  
  
  
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
   
 
  
        
     
  
     
   
   
       
        
  
  
    
  
   
  
    
    
    
      
 
    
    
   
      
  
   
   
  
  
      
         
  
      
  
     
      
  
  
   
    
  
  
      
 
  
    
      
  
       
       
  
     
          
     
      
   
     
  
      
  
     
    
      
  
    
     
   
    
     
     
     
  
      
 
                
        
  
  
  
 
    
    
    
    
  
  
  
  
  
  
    
   
         
    
  
        
        
   
 
   
  
        
    
  
  
 
      
    
    
      
      
 
   
        
    
   
  
     
       
  
  
          
   
  
    
  
     
    
  
 
  
 
  
 
  
  
    
           
  
   
   
  
   
  
         
      
 
    
  
    
      
  
  
  
      
  
        
       
                   
  
    
     
    
       
     
    
  
   
    
     
      
  
   
      
 
     
    
      
  
  
  
   
    
  
    
      
  
    
  
  
  
     
  
        
     
    
     
        
    
   
      
   
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
 
  
  
 
  
    
   
             
   
 
     
  
  
 
  
  
 
    
  
     
  
           
   
 
      
     
      
    
   
    
     
  
   
    
      
  
  
  
    
 
  
    
   
  
        
   
 
   
  
    
    
  
   
  
  
  
 
  
  
  
   
    
    
  
                       
  
  
           
 
  
  
 
  
   
  
  
     
 
 
  
 
       
  
   
  
    
  
  
      
                        
  
  
  
  
  
      
    
    
  
    
  
  
 
 
    
  
 
 
  
  
 
  
  
    
 
  
    
 
 
  
  
  
   
  
  
    
   
    
 
  
 
  
 
   
      
   
   
  
     
  
       
   
  
      
    
                
   
  
  
      
   
  
  
      
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
 
  
 
 
  
      
  
    
        
     
  
  
  
  
  
                 
    
         
          
     
                
   
  
   
  
    
    
    
    
   
     
  
              
   
    
 
    
    
      
      
    
            
     
  
   
     
    
   
  
      
 
  
  
  
      
        
   
 
  
  
 
 
 
 
   
  
  
  
        
  
 
  
   
   
      
  
   
  
      
     
  
  
       
  
  
   
   
  
  
    
  
  
  
 
    
   
 
   
  
 
  
 
 
  
  
  
    
    
 
   
  
 
  
 
  
  
  
 
  
  
  
    
 
 
    
 
 
  
 
  
  
  
   
  
  
     
  
    
  
  
    
  
     
 
      
    
   
  
        
   
     
     
        
     
     
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
 
  
  
   
 
      
  
   
   
    
  
  
 
  
  
      
    
     
    
 
 
 
  
      
  
  
 
  
  
 
  
  
  
  
 
  
  
   
     
    
    
     
 
       
     
  
        
    
 
  
  
      
     
    
    
  
 
        
      
  
  
      
   
  
   
  
    
    
    
    
    
     
  
  
  
  
   
    
      
  
 
      
    
     
  
  
    
   
      
        
      
    
 
        
     
  
   
  
  
 
    
  
  
  
      
    
     
    
 
 
  
  
   
          
  
  
    
   
  
 
  
 
  
      
    
   
  
  
   
  
    
     
  
  
       
   
     
     
  
  
      
  
    
 
  
     
    
 
  
   
    
 
    
          
  
        
    
 
 
  
      
     
   
 
 
    
    
  
 
       
      
  
  
      
   
 
  
     
   
  
    
       
 
  
  
    
    
    
  
  
   
  
 
    
  
 
  
  
  
  
      
          
     
  
    
     
  
    
  
  
     
         
   
  
  
    
    
  
  
  
    
 
  
  
  
  
 
    
  
 
  
  
  
    
  
    
   
 
  
       
    
   
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
  
    
 
   
      
     
  
      
    
 
    
  
    
 
  
     
     
        
   
    
    
  
    
   
     
  
  
  
            
    
     
  
    
  
      
     
   
   
  
         
     
     
  
     
       
  
     
     
      
      
            
    
   
    
   
     
      
      
  
   
  
      
    
      
     
  
      
   
    
    
        
  
     
      
      
         
     
   
      
       
           
 
 
  
 
  
  
    
  
        
  
  
 
   
  
    
  
    
    
 
              
      
     
  
  
      
    
  
  
 
   
   
     
  
    
  
 
 
  
    
    
  
  
 
      
  
        
        
 
        
  
     
   
    
 
    
     
      
   
     
    
 
      
    
    
     
   
    
  
 
 
   
  
  
 
 
   
    
  
  
    
   
     
  
    
    
  
    
  
    
      
      
 
  
  
 
     
  
    
  
  
  
  
     
    
      
      
  
 
             
              
   
   
  
     
  
           
      
 
    
    
           
     
  
  
   
            
         
     
 
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
     
       
         
 
  
 
    
    
       
    
  
   
    
  
    
     
  
    
  
     
  
     
    
  
   
 
 
 
    
  
    
    
  
  
   
 
    
      
     
    
    
   
     
  
    
  
            
   
  
  
    
         
    
   
                  
    
    
   
      
           
     
  
   
  
    
  
  
 
         
 
        
  
    
  
       
     
  
     
     
     
  
       
      
   
    
    
  
    
 
 
    
 
  
  
  
       
  
    
    
 
  
 
 
     
 
     
 
  
     
 
  
 
 
  
 
  
    
    
  
 
  
    
   
  
    
  
    
 
 
  
  
   
  
         
    
  
      
   
   
   
  
  
    
    
     
  
  
  
  
 
       
  
  
      
    
    
  
  
    
    
             
 
             
      
   
    
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
  
   
     
 
 
 
    
  
 
  
  
  
       
  
    
    
 
  
 
 
  
      
 
  
 
 
    
 
  
    
        
          
  
  
    
 
    
        
    
      
  
 
               
        
    
     
   
    
  
    
  
   
     
 
 
  
 
  
  
  
       
  
    
     
 
  
 
   
     
  
      
  
      
  
   
    
     
      
   
 
 
 
  
      
     
  
    
      
   
     
  
  
  
   
 
  
 
  
      
  
 
  
  
           
    
  
     
  
  
  
    
      
  
  
                 
                
 
              
                      
                     
  
      
 
  
  
      
  
   
  
  
  
  
  
    
  
    
    
    
 
               
   
     
 
    
  
  
     
  
      
 
  
          
     
      
    
 
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
  
  
 
 
   
    
      
  
          
   
      
   
  
  
    
  
    
 
  
    
      
           
   
   
 
            
      
  
    
   
 
  
      
     
   
   
 
    
 
 
 
    
   
  
 
  
  
      
 
 
                
  
  
       
  
    
        
      
           
                  
  
       
  
  
         
    
   
  
     
  
    
  
  
      
     
 
   
  
    
   
  
    
  
     
   
   
  
  
      
  
  
   
     
  
    
    
  
  
 
    
      
     
  
 
    
  
  
  
 
 
  
 
 
   
  
      
                
     
  
     
  
        
  
      
          
  
   
 
  
  
      
            
    
                
           
               
        
     
 
  
  
    
    
           
   
   
      
   
      
    
    
  
    
     
  
    
   
  
 
 
  
  
    
  
    
    
     
      
      
   
                
       
                
        
                       
  
       
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
        
      
    
    
  
    
   
  
  
  
    
  
    
  
   
  
            
  
    
  
  
 
  
  
        
    
      
    
  
 
 
        
      
    
   
       
                   
      
    
    
   
  
  
  
    
  
       
    
 
  
  
        
  
    
  
   
  
    
           
  
   
       
          
  
           
 
      
     
  
  
  
  
 
 
  
 
      
    
  
        
  
      
 
                       
  
      
 
    
  
    
    
    
  
  
  
  
 
  
  
  
    
  
  
  
  
     
      
       
  
    
  
  
 
 
  
  
  
    
 
   
   
  
   
     
     
  
 
     
 
 
 
  
    
 
   
 
 
  
  
 
  
  
  
    
  
  
       
     
  
    
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
  
  
 
 
  
 
 
   
  
  
  
  
  
  
 
    
  
  
    
  
   
  
  
  
  
  
  
 
  
  
  
 
  
 
 
 
  
  
 
 
    
  
  
  
  
  
 
  
  
  
  
  
  
 
 
  
  
    
  
 
      
    
    
   
      
  
    
  
 
 
 
  
  
  
    
  
 
  
  
    
  
    
  
   
  
            
  
    
  
  
 
  
 
      
  
  
  
  
     
  
  
 
    
     
  
    
    
     
  
  
 
        
    
  
 
     
  
  
   
  
  
   
  
     
  
  
  
     
  
   
 
      
  
          
  
   
  
  
 
  
 
   
  
  
   
    
  
  
   
 
        
    
  
           
  
    
  
 
      
    
 
    
     
    
                
             
   
  
  
    
 
      
   
  
 
  
 
   
  
   
  
           
   
  
      
  
  
  
    
   
  
      
   
         
  
   
  
  
  
  
  
  
       
  
   
  
    
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
        
  
  
    
  
    
   
 
     
      
  
  
  
    
  
  
    
   
      
      
  
   
  
  
    
     
    
  
  
   
  
  
      
  
  
     
    
      
   
  
      
  
  
     
 
   
  
 
 
  
  
  
 
 
     
      
  
  
    
  
  
 
  
 
  
  
    
    
 
        
      
    
    
   
  
  
  
    
  
  
        
 
  
  
     
  
    
 
  
  
  
  
    
     
    
  
 
  
     
        
        
     
  
 
  
  
     
     
            
      
   
     
    
     
    
   
   
          
      
    
 
      
      
  
  
  
  
  
    
   
  
  
  
    
    
     
    
             
   
    
   
  
  
    
  
   
  
  
  
 
  
  
  
      
   
    
     
        
    
   
  
     
         
  
  
  
   
    
      
     
    
   
  
              
    
  
    
   
  
  
     
  
  
      
    
  
   
       
          
 
  
 
      
         
  
  
          
 
        
    
  
    
   
   
                     
           
    
  
    
  
  
        
    
   
  
 
        
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
    
   
        
    
 
   
  
  
     
  
     
  
 
 
  
      
      
      
  
 
     
  
 
  
      
      
  
    
 
    
    
 
  
    
  
  
    
  
  
 
 
  
  
   
  
  
 
  
    
    
  
      
 
 
    
   
  
  
  
 
  
 
  
   
 
  
  
  
 
  
    
  
    
  
  
     
  
  
    
   
  
    
 
 
    
   
  
     
  
    
  
    
    
  
 
      
  
 
  
      
      
  
  
    
 
  
  
          
    
 
  
  
  
    
   
      
      
    
  
 
 
  
     
     
        
      
  
 
     
  
 
  
            
  
    
    
     
      
   
  
      
  
   
       
    
   
         
    
        
    
  
   
    
   
  
    
 
 
     
     
   
  
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
   
  
  
   
    
  
 
 
 
     
  
  
 
    
  
  
  
  
    
  
     
 
         
  
  
   
     
 
  
  
   
  
 
    
  
    
  
 
 
  
    
  
  
  
    
    
   
     
  
  
    
  
     
  
    
  
    
  
   
    
  
  
  
    
    
   
 
    
  
      
      
   
    
 
  
    
     
    
  
     
  
    
    
  
      
     
     
  
      
  
      
        
  
  
   
    
    
 
    
  
  
      
    
  
        
  
  
    
    
     
  
  
  
 
 
  
  
          
  
     
         
  
 
  
  
      
   
    
   
     
 
  
  
      
    
     
 
  
  
  
  
  
  
      
  
 
  
  
  
    
   
  
    
   
    
   
  
 
 
  
  
      
  
    
   
  
   
  
  
  
  
    
   
  
   
  
  
    
     
  
  
  
 
  
  
 
 
 
     
    
  
       
        
         
  
 
  
 
 
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
    
   
 
 
 
   
 
 
  
  
  
 
  
  
  
  
 
 
  
  
        
   
   
    
 
      
      
  
    
  
 
      
    
      
  
  
  
      
  
     
  
     
  
 
  
 
  
  
  
     
      
  
  
    
        
   
 
   
  
     
      
    
  
 
  
    
         
        
  
 
  
    
 
         
     
  
      
      
    
  
     
  
      
 
        
              
      
   
   
    
  
  
  
       
       
     
 
     
     
 
 
    
  
  
    
  
   
       
     
  
    
  
  
  
  
  
 
  
  
  
  
      
  
  
   
 
      
      
    
           
 
  
    
  
     
     
  
    
 
    
         
   
  
      
  
 
    
    
        
    
    
     
  
   
  
     
     
        
    
       
  
  
  
           
      
  
  
  
    
  
  
    
  
  
  
  
   
        
  
      
     
  
    
       
    
  
    
  
     
      
  
    
    
            
   
  
      
        
    
   
    
   
    
   
  
 
 
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
   
  
  
    
  
 
  
  
   
             
  
   
 
         
    
  
  
         
     
  
  
         
     
 
    
     
    
    
      
     
  
   
    
  
  
      
 
  
   
    
  
    
  
 
  
   
    
      
  
   
   
   
       
  
   
    
  
      
 
  
      
       
  
  
       
       
  
   
    
  
     
  
  
  
  
      
  
   
  
 
 
 
 
   
  
  
  
  
    
    
   
 
  
     
    
  
    
    
 
    
    
   
    
   
 
  
      
  
     
  
    
 
  
    
   
     
  
  
     
         
   
  
  
  
    
                 
    
 
      
     
     
    
     
   
  
  
     
      
  
      
 
    
         
  
  
    
 
    
  
        
            
 
  
      
     
    
     
 
    
          
      
  
  
     
     
    
      
      
     
   
     
      
    
     
    
  
      
              
    
  
  
 
  
  
    
         
  
  
 
 
   
  
  
  
   
 
      
  
                  
      
  
   
  
  
  
  
    
  
  
        
     
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
  
    
    
  
 
  
    
  
  
  
   
         
 
   
    
      
    
    
   
  
    
     
     
  
  
    
   
                
   
     
  
 
    
    
    
      
  
      
 
    
  
      
    
  
     
      
 
    
      
 
    
  
      
  
    
  
    
 
    
  
      
  
    
  
     
   
  
    
    
   
 
    
    
  
    
    
  
    
 
    
  
  
   
    
      
    
 
           
    
           
 
    
      
     
     
      
 
     
    
    
  
    
   
  
      
  
    
   
 
    
     
  
   
 
    
    
 
    
    
  
  
  
     
  
     
  
     
      
  
  
    
  
  
 
   
  
    
  
  
  
    
    
  
    
  
  
  
    
    
  
      
      
    
  
    
 
  
  
    
     
    
  
      
  
  
  
  
     
 
  
        
     
  
     
  
      
  
  
     
    
   
  
        
    
  
      
    
 
  
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
   
 
   
  
  
 
 
   
   
   
        
  
  
  
  
    
  
    
  
   
  
          
       
    
     
      
     
    
    
  
 
   
      
    
  
    
  
 
  
    
    
      
  
  
 
      
       
    
    
    
 
  
   
      
      
     
  
  
    
          
  
      
    
    
    
    
  
     
    
           
      
    
  
 
   
      
      
  
   
  
  
     
  
  
    
    
  
  
  
  
  
 
  
    
     
       
    
   
    
  
   
  
  
    
  
 
   
    
   
  
       
  
  
     
  
    
  
  
  
  
     
     
            
  
 
  
  
  
    
     
  
    
 
        
    
  
          
 
    
    
    
  
     
   
 
    
      
   
       
      
 
  
  
  
    
    
      
   
    
    
 
       
   
         
    
  
    
    
   
        
    
  
  
  
  
  
    
  
  
  
    
  
      
  
  
   
 
    
  
    
    
  
  
  
 
  
    
   
        
    
      
   
  
  
      
     
       
 
  
  
   
  
  
  
  
   
  
    
  
   
  
    
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
      
  
   
         
    
 
 
  
   
  
  
    
 
  
  
 
  
       
      
  
 
   
    
    
    
  
   
  
 
 
       
   
    
  
  
     
  
     
  
  
  
  
 
      
  
     
   
   
     
 
  
           
    
      
 
  
      
   
   
  
  
   
  
   
   
      
  
      
 
         
  
       
      
  
          
    
    
    
   
  
  
     
   
  
 
 
  
 
  
 
 
        
     
          
  
   
  
  
      
      
 
  
  
    
  
      
      
  
      
      
        
  
      
      
        
  
      
       
      
        
      
        
  
 
     
     
   
    
  
  
      
   
   
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
  
  
    
  
  
 
  
    
  
 
 
 
  
  
  
  
 
  
  
   
  
   
 
 
 
         
    
  
   
     
  
       
      
      
      
        
        
       
   
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
  
 
  
  
    
      
   
   
    
   
  
      
  
 
        
            
    
    
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
 
  
 
  
 
 
  
  
      
      
      
    
 
 
  
  
  
      
    
  
   
      
    
     
     
  
   
 
      
     
    
    
      
 
    
           
            
       
  
  
  
  
  
  
  
  
      
    
    
  
  
  
  
  
  
  
  
   
  
   
  
  
  
      
   
    
  
      
   
     
   
 
  
  
        
       
    
  
   
  
  
  
    
  
        
  
   
    
  
    
  
  
  
      
 
  
   
  
    
  
      
  
 
  
      
    
  
      
  
 
  
     
    
  
   
          
     
  
  
      
  
    
  
       
   
   
    
      
    
  
 
  
        
    
      
    
   
      
    
    
  
      
    
 
 
   
  
  
    
   
  
  
      
  
  
  
  
 
    
      
  
    
     
             
  
  
 
  
    
      
  
      
   
   
  
   
       
    
   
  
 
  
  
      
   
      
  
  
   
 
      
  
   
  
  
        
   
  
    
 
    
  
    
  
  
  
         
   
    
  
   
  
        
    
     
  
  
    
 
     
  
    
      
            
   
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
     
  
  
     
      
    
   
  
     
  
        
  
    
  
   
     
  
  
    
      
  
    
      
  
           
  
 
     
  
            
  
  
        
  
      
     
   
     
  
 
    
  
     
  
  
  
  
       
     
    
      
  
    
    
 
     
    
     
  
    
     
  
  
   
  
     
      
  
   
    
    
      
     
     
 
  
  
    
  
      
  
      
 
  
    
         
       
  
   
      
  
    
  
      
  
     
    
  
  
  
      
    
  
      
 
    
  
  
      
     
  
  
     
  
      
  
          
 
     
     
   
  
  
   
  
      
  
   
       
     
 
   
  
      
          
  
    
     
 
        
    
  
        
    
 
    
    
    
       
   
     
  
             
     
  
   
      
     
  
    
  
  
  
    
    
    
  
      
  
 
    
   
        
      
    
 
   
  
    
  
      
  
  
  
 
   
     
   
  
  
    
  
    
  
  
   
 
  
   
   
 
 
 
  
    
 
  
    
 
  
  
   
  
    
 
 
  
    
 
 
  
    
 
 
  
    
 
 
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
 
 
  
  
  
      
      
  
    
 
 
    
 
 
  
  
  
    
    
   
       
  
   
  
  
  
    
      
      
   
    
 
    
  
     
   
    
    
  
  
  
  
    
  
    
        
  
      
      
  
     
   
  
  
  
  
      
   
    
   
  
 
    
  
    
  
      
    
  
                
  
 
  
      
  
    
  
 
  
    
  
  
 
  
    
  
 
   
  
  
    
    
        
          
    
  
   
   
            
  
  
    
  
  
    
          
  
  
    
            
  
   
        
    
     
    
   
    
  
 
          
      
  
   
  
   
   
      
    
  
  
 
    
  
     
  
    
    
  
 
  
          
    
   
    
 
      
      
    
  
   
  
 
    
      
      
  
  
  
    
   
      
  
  
     
 
      
        
  
  
    
 
 
    
  
        
      
 
 
  
    
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
    
    
  
 
        
  
  
    
  
    
      
   
    
    
     
    
     
     
  
      
    
  
      
  
 
    
  
  
  
  
 
  
    
      
  
    
  
  
  
 
 
       
      
  
    
   
 
            
    
  
    
   
  
 
    
        
  
    
    
      
 
    
  
  
 
  
 
  
    
      
      
    
    
 
      
  
    
   
     
        
    
  
    
   
  
 
  
  
        
  
    
  
 
      
      
  
  
  
  
 
          
  
    
  
             
 
  
  
  
  
  
 
  
  
  
           
   
  
 
  
    
  
  
  
  
    
  
    
      
    
  
      
      
     
   
   
  
  
    
    
  
  
 
   
  
     
 
  
    
      
 
  
        
 
  
    
      
 
  
        
  
  
  
  
        
        
    
  
      
       
   
 
     
    
   
    
  
    
   
    
       
   
  
     
  
  
  
    
  
    
      
    
  
      
      
       
   
 
    
  
        
  
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
   
  
    
 
 
    
 
  
    
 
      
   
      
 
  
  
  
        
 
  
   
    
 
  
        
 
  
        
 
       
  
  
    
  
    
  
  
    
      
      
     
     
  
    
   
  
   
  
  
 
  
  
  
  
    
  
  
  
   
  
          
   
  
   
        
     
   
  
            
     
  
    
            
   
 
  
      
  
    
  
  
  
    
            
     
    
   
     
    
           
    
  
  
     
  
  
   
        
 
  
    
    
    
    
            
      
 
   
  
         
    
   
    
 
           
    
     
     
 
     
      
  
  
     
     
            
 
       
    
     
  
       
            
     
        
   
     
  
        
        
   
  
    
  
  
  
   
  
  
      
        
     
   
  
  
  
    
   
  
     
  
     
  
        
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
     
    
  
    
  
    
 
   
  
          
 
       
    
     
  
     
   
  
    
   
  
  
       
      
  
      
     
    
    
     
  
     
     
  
    
   
 
     
      
  
  
  
   
  
      
 
       
    
     
  
     
      
  
    
  
    
   
  
  
  
     
      
  
  
    
   
  
 
       
    
     
  
     
      
  
    
  
    
 
    
  
  
     
    
       
    
     
  
     
   
    
       
       
   
  
  
  
        
     
   
        
  
  
   
  
  
  
        
     
   
  
  
  
       
  
     
  
     
  
  
    
        
   
  
  
  
     
     
  
 
       
    
     
  
     
     
  
    
    
   
   
    
    
   
    
    
     
   
      
    
   
  
     
   
  
  
 
      
   
    
  
  
  
   
 
  
      
  
    
          
 
  
   
  
  
   
        
     
  
          
       
  
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
  
    
  
   
 
 
     
   
  
    
  
  
  
  
  
 
  
  
 
    
    
  
  
 
     
   
     
  
    
 
 
  
 
  
  
    
 
   
  
     
  
     
       
   
  
  
    
 
      
   
    
  
    
 
    
  
   
    
  
 
   
    
  
 
  
 
 
  
  
  
        
     
  
   
 
  
  
  
  
           
   
  
  
      
  
  
 
  
 
   
    
    
  
    
  
    
           
     
  
  
 
  
 
    
  
    
     
  
         
 
 
    
  
    
  
      
  
  
    
      
   
  
      
  
   
     
    
  
  
          
      
  
  
    
  
 
    
           
     
  
  
  
  
 
  
   
  
  
      
      
      
 
   
     
  
              
  
    
         
     
  
  
   
    
  
 
  
   
  
    
        
   
 
   
        
  
  
    
  
            
    
      
     
    
         
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
      
   
                 
   
   
    
    
  
 
   
    
  
          
    
  
  
      
  
  
 
  
  
   
  
  
  
    
           
       
  
     
  
  
    
  
            
    
      
     
      
         
         
    
   
  
 
  
           
    
  
  
 
  
  
  
 
  
  
      
 
  
  
  
  
      
           
  
  
    
    
            
      
 
  
  
    
  
            
    
      
     
       
  
   
    
           
       
  
            
  
      
    
 
  
     
     
            
 
  
  
    
  
            
    
      
     
      
     
 
      
  
  
   
  
  
      
        
    
    
   
  
    
     
  
   
  
    
        
  
   
    
 
    
     
  
      
  
     
      
  
  
  
   
  
      
 
    
     
  
      
  
     
      
  
  
    
   
  
 
    
     
  
      
  
     
    
    
     
  
      
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
   
  
  
  
        
 
                
   
    
             
    
   
    
  
   
    
  
       
    
    
  
  
      
  
  
 
  
  
   
  
  
    
        
  
                
    
    
 
                 
    
 
  
   
  
  
  
    
    
    
  
  
      
  
 
 
  
  
         
  
     
     
  
 
    
     
  
      
  
  
 
   
    
    
   
   
   
      
     
    
      
   
  
      
  
     
   
  
  
 
    
     
  
      
  
  
    
  
    
  
   
 
 
  
        
    
  
           
 
  
   
      
  
    
  
 
  
  
  
  
   
  
  
  
  
 
  
  
 
    
   
  
 
  
        
  
             
   
  
  
   
  
  
  
 
  
  
          
  
  
 
  
 
  
      
    
  
      
      
 
    
  
  
    
        
   
      
     
  
            
  
  
  
   
    
        
    
     
   
      
      
  
    
     
        
    
   
  
    
    
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
      
        
 
   
   
       
     
  
  
  
    
   
    
      
  
  
 
  
    
          
      
  
   
    
   
  
  
  
      
      
   
  
              
    
       
  
  
  
      
  
  
  
 
         
  
  
   
      
   
      
    
  
      
    
  
  
         
  
    
     
  
  
   
  
  
 
     
    
  
   
      
   
      
    
  
      
    
  
  
         
  
    
     
  
  
  
       
     
          
 
     
      
           
   
  
      
  
  
 
 
      
   
    
     
   
  
  
    
     
      
       
    
    
    
      
      
   
  
 
 
  
 
  
  
        
  
    
  
    
      
  
  
  
    
  
   
       
  
  
      
    
      
  
 
    
  
  
  
  
     
   
  
  
    
     
  
 
  
    
   
    
  
  
  
 
  
      
     
       
  
    
 
 
 
  
  
    
  
        
 
 
  
  
     
    
  
      
      
    
    
  
    
    
    
 
      
  
      
   
     
    
  
      
       
        
  
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
  
      
       
    
  
     
   
  
   
    
  
          
 
 
    
  
    
   
    
 
    
  
    
    
        
        
   
  
  
  
  
 
  
  
  
  
 
 
  
    
                      
      
      
      
    
  
   
   
                 
      
    
      
    
  
        
  
     
  
  
        
      
  
      
 
    
  
  
    
  
        
     
  
  
   
  
  
 
   
    
 
  
      
      
     
    
  
   
 
  
      
       
   
 
  
      
 
  
      
      
    
  
      
    
  
   
  
  
 
 
 
 
  
    
      
      
   
  
     
  
    
        
  
      
    
        
   
 
 
 
  
    
  
      
       
  
  
  
 
  
     
      
  
      
      
 
      
  
  
 
  
  
   
      
     
  
  
   
 
 
  
    
  
      
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
      
 
  
      
   
      
  
  
 
 
  
  
      
          
   
 
  
    
    
  
  
  
      
 
      
     
   
  
   
  
    
 
  
    
    
  
        
    
   
   
     
  
  
      
     
      
  
    
      
      
 
              
  
  
      
   
    
    
      
  
  
      
   
     
     
  
    
      
    
     
      
  
  
      
    
  
    
  
  
  
  
    
    
  
  
  
 
  
    
  
     
     
   
  
   
    
    
      
  
    
   
     
    
   
    
  
  
    
     
      
  
  
  
   
 
  
 
      
       
      
    
   
 
       
    
        
    
 
    
          
          
    
  
  
 
 
    
  
  
    
   
    
     
      
  
  
    
      
 
    
   
    
    
      
 
    
        
    
     
   
    
  
  
     
  
    
    
      
      
        
  
    
 
      
          
  
  
     
 
      
      
    
      
   
    
    
  
   
   
     
    
  
  
   
    
 
  
    
        
  
  
   
   
  
      
  
    
  
    
  
          
    
  
      
        
      
  
    
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
      
      
    
  
    
   
  
   
      
    
       
  
  
  
  
 
  
    
    
       
      
   
  
 
      
      
    
  
     
     
     
    
  
  
  
 
   
    
    
 
  
  
  
 
        
    
    
      
  
    
 
    
  
   
  
  
   
  
   
  
    
   
  
      
    
  
   
  
    
  
  
   
  
  
    
  
 
   
  
  
 
 
    
  
    
      
  
      
   
  
    
    
    
      
     
    
      
    
      
       
    
  
      
  
     
   
   
  
  
  
  
    
    
      
   
  
 
      
      
  
    
    
  
         
    
  
    
     
  
  
    
     
   
  
        
    
      
  
      
  
  
    
    
     
      
   
  
  
    
        
  
    
       
  
       
  
      
       
           
     
       
   
       
  
 
    
    
    
       
  
    
    
 
      
   
            
        
 
      
       
     
  
      
  
   
  
    
  
 
 
  
    
    
  
    
 
         
  
        
   
  
 
    
  
  
    
        
  
      
 
  
    
  
         
    
  
 
  
  
  
  
           
    
  
    
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
      
       
     
   
 
    
  
 
   
  
 
  
   
 
 
  
    
  
  
     
  
   
  
  
    
  
  
      
  
 
    
    
        
  
    
   
   
  
  
  
     
      
 
    
 
     
      
  
    
      
      
   
    
   
    
 
  
    
     
  
      
      
     
     
  
    
     
  
    
  
      
   
  
    
  
  
  
  
 
  
        
   
  
      
  
  
 
    
  
  
   
  
 
   
  
 
  
   
    
  
   
  
   
  
 
  
  
   
 
 
 
  
  
  
  
  
 
 
  
      
      
  
      
 
     
    
      
    
 
  
  
  
    
      
 
   
    
      
  
 
 
    
  
    
              
  
  
  
  
         
     
  
    
  
 
   
  
    
     
   
  
    
   
     
  
  
   
 
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
   
  
   
    
    
  
   
 
  
  
  
  
  
   
  
    
    
  
     
  
  
  
  
    
  
    
    
   
    
      
    
  
 
  
    
  
    
    
     
  
   
     
       
    
  
    
  
 
    
   
     
  
    
   
  
  
    
    
   
  
    
    
 
    
  
       
  
  
     
    
 
      
      
  
    
   
  
   
    
  
 
  
  
    
  
    
  
    
 
    
     
  
  
  
 
    
 
  
    
       
      
  
     
   
            
  
  
    
  
      
  
  
       
     
  
     
    
  
    
    
  
  
    
   
   
    
 
     
  
  
  
  
  
    
      
   
  
     
  
      
    
   
    
   
    
  
     
    
  
   
  
     
      
            
 
        
  
  
    
    
  
   
      
    
   
  
     
  
   
  
  
  
      
   
   
  
  
    
    
    
    
   
  
   
   
  
   
    
      
        
  
  
  
  
  
 
 
  
    
      
      
    
  
 
   
    
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
 
  
  
      
   
            
   
 
  
  
    
      
  
   
   
  
    
  
     
  
    
   
 
    
  
          
 
  
  
           
   
  
      
      
   
      
  
  
  
    
     
             
    
       
   
 
          
       
    
     
  
    
   
      
    
      
  
  
  
      
    
    
  
  
 
    
    
  
   
    
  
  
  
    
 
  
    
    
    
  
  
    
 
 
    
  
  
  
   
      
 
  
        
  
    
   
     
    
    
  
  
  
  
      
   
      
     
   
      
  
   
             
   
  
  
  
  
  
    
  
  
      
     
     
  
  
       
      
  
  
    
  
 
  
  
  
  
      
     
  
   
    
  
       
   
 
  
               
  
  
      
   
         
   
    
    
    
 
    
    
  
      
          
   
   
        
   
  
   
  
  
   
   
  
  
    
  
         
  
  
     
      
     
  
  
  
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
  
 
  
    
  
    
      
    
 
 
    
      
  
 

 
 
 
  
  
 
  
   
 
 
 
 
 
 
      
 
  
 
  
    
    
  
   
   
  
   
 
    
   
  
  
 
  
   
  
  
  
    
  
   
   
  
  
    
   
    
    
   
     
  
  
  
    
   
  
  
    
  
    
    
  
   
  
       
    
      
  
   
     
  
  
    
  
  
 
  
  
    
  
    
  
        
 
 
 
 
  
    
    
       
    
      
  
  
   
  
  
   
 
    
 
  
  
    
    
     
  
    
   
  
   
    
  
  
   
  
 
     
  
    
    
       
  
   
   
      
   
    
  
 
  
    
    
  
  
  
    
    
   
    
   
    
 
  
   
    
  
  
   
  
  
   
   
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
    
  
 
 
  
  
  
  
  
    
  
    
 
    
  
   
    
      
  
                 
  
      
   
   
  
     
  
   
  
  
  
  
   
  
  
   
    
   
    
  
    
  
   
   
  
  
  
     
  
    
     
  
 

 
 
 
  
  
 
  
   
 
 
 
 
 
 
      
  
    
   
      
  
  
 
   
  
  
    
 
  
    
  
    
 
  
  
  
   
 
  
    
    
   
  
    
 
 
  
  
    
    
  
 
 
  
  
  
  
   
  
    
 
  
  
   
   
  
     
    
    
   
    
       
   
   
   
  
    
   
  
 
  
   
  
  
   
    
    
    
         
  
  
  
  
        
  
  
    
  
  
    
   
  
 

 
 
 
  
  
 
  
   
 
  
 
  
     
    
    
  
 
 
  
 
  
 
  
   
   
   
   
    
    
  
  
  
  
 
 
 
  
  
    
  
  
  
    
  
  
  
       
 
  
  
 
   
   
    
   
    
   
   
   
   
   
   
   
   
   
   
  
 
   
  
        
              
  
  
  
  
  
             
  
  
  
        
              
  
  
  
  
  
             
 
  
        
              
  
  
  
  
  
             
  
 
 
        
              
  
  
  
  
  
             
  
  
     
 
        
              
  
  
  
  
  
             
 
  
        
              
  
  
  
  
  
             
    
  
  
        
              
  
  
  
  
  
             
   
  
  
   
   
  
          
  
  
  
  
  
             
 
 
  
 
 
 
  
  
 
 
 
   
 
   
  
  
 
 
  
 
 
 
   
 
 
 
  
 
 
 
   
  
 
  
 
  
 
   
   
  
  
 
  
                          
  
  
  
  
      
     
 
 
 
  
  
  
  
 
  
  
 
  
  
 
  
   
   
  
   
           
  
                   
   
 
  
  
 
   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
  
  
  
  
  
      
  
  
  
  
  
  
  
 
  
 
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
   
 
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
  
    
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
   
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
    
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
     
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
    
 
  
   
 
  
  
   
           
  
                 
  
  
 
 

 
 
 
  
  
 
  
   
 
  
 
  
     
    
 
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 
  
                          
  
  
  
  
      
  
 
  
  
  
 
    
  
  
      
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
  
  
  
      
  
  
  
  
  
  
  
 
     
       
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
  
  
   
 
 
  
  
      
              
  
  
  
  
  
  
  
 
     
   
  
 
       
  
  
        
   
   
  
 
     
 
   
   
     
  
   
  
        
   
     
      
 
   
  
    
   
    
     
  
    
       
  
  
    
              
    
          
   
      
            
   
  
      
   
               
               
      
    
                
 
           
  
      
           
   
       
   
   
            
         
       
  
  
   
  
     
  
   
        
      
     
  
    
   
  
        
      
        
  
 
  
  
       
     
  
      
    
  
       
  
      
    
     
   
  
      
      
   
   
       
               
  
  
       
  
    
        
      
                              
 
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
 
 
 
 
  
 
  
   
 
 
 
    
 
 
  
   
   
    
   
  
    
 
       
  
  
    
      
   
   
  
  
    
  
    
  
   
  
 
 
 
    
  
                            
 
  
   
 
       
  
  
      
  
         
 
  
   
       
       
  
  
      
  
            
  
  
     
  
    
  
    
 
  
  
   
   
 
       
  
  
      
  
         
 
           
  
    
      
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
    
  
 
 
 
 
 
 
 
 
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
    
  
  
 
 
  
    
  
  
        
   
 
 
    
    
  
    
    
  
 
  
  
  
  
  
  
  
  
    
  
 
  
  
    
  
  
  
   
  
  
      
  
 
            
                 
  
        
     
   
 
                   
  
    
   
    
  
  
    
  
     
  
  
    
     
  
      
   
 
    
    
  
       
  
   
    
 
  
      
   
  
  
  
 
  
    
  
  
  
  
  
    
      
  
     
  
    
   
    
  
   
  
  
  
  
  
  
  
    
       
  
     
     
    
  
  
  
    
  
  
   
   
    
  
     
  
  
  
  
      
     
      
         
  
   
      
      
  
  
  
  
     
      
   
  
  
  
    
  
  
  
  
  
 
   
  
    
           
     
  
  
 
 
        
    
  
        
  
  
 
  
     
  
    
     
  
  
 
  
  
  
 
  
  
 
  
        
 
  
   
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
  
    
  
  
     
  
 
 
 
 
 
 
  
  
 
  
  
 
  
  
  
 
  
     
 
  
   
  
    
    
     
 
  
 
  
    
  
     
 
 
    
 
  
    
  
    
 
    
           
  
  
  
   
 
  
  
  
    
   
    
 
 
  
  
  
  
 
        
    
  
    
   
  
  
                   
 
  
    
  
  
  
  
                  
      
    
   
     
       
     
    
     
  
  
     
  
    
  
    
   
  
        
    
    
   
    
 
  
    
  
      
  
  
     
  
  
 
  
        
    
  
        
   
  
          
  
  
  
  
  
   
  
  
  
    
   
    
  
     
  
  
  
 
  
      
  
  
  
 
      
      
   
  
 
           
  
    
  
    
  
  
    
  
  
   
  
    
 
  
 
 

 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
           
    
         
    
 
 
      
  
    
   
   
  
  
    
  
      
  
  
 
    
  
  
                 
         
     
  
  
    
  
    
  
  
    
  
  
   
  
    
 
  
 
                   
  
    
   
    
  
  
    
  
     
  
  
      
  
  
    
 
    
  
  
   
    
  
 
                 
  
    
    
 
 

 
 
 
     
 
 
 
  
  
 
  
  
  
  
   
  
  
  
    
     
 
    
   
      
  
        
   
        
 
 
  
  
  
 
  
   
  
    
   
 
 
 
 
  
 
 
  
  
  
    
   
  
        
     
 
 
 
   
  
    
  
   
  
  
 
  
 
  
 
  
 
 
 

Signature Page 
Document Information 
Short Title :  
 
 
Name : 
 
 
 
Object ID : 
 
 
 
 
 
 
Signature 
 
Date : 
 
 
(GMT) 
Signed by : 
 
(Name and ID) 
Justification : 
 
 
 
 
 
Electronic signature page generated by MIND 
 
E_PC_T0832_Ph3 DBT-HR_Ed03_Approved
Approved as 
Clinical Study Protocol: T0832, Phase 3 HR study-Amendment 02
Oct 31, 2016 05:34:00
PPO
PPO
CPI