Clinical trial NCT03714776
Conditions: Mild Hypertension
Keywords: Hypertension Hypertensive AGT Angiotensinogen Blood Pressure High Blood Pressure
Sponsor: Ionis Pharmaceuticals, Inc.
Start date: 2019-01-03; Completion date: 2019-11-13
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a Phase 2, double-blind, randomized, placebo-controlled study of IONIS-AGT-LRx conducted in mild hypertensive participants.

Detailed description:
Participants were randomized in a 2:1 ratio to receive a once-weekly subcutaneous treatment and an additional loading dose on Study Day 3 with either IONIS-AGT-LRx or placebo for 6 weeks.

All participants completed a 13-week Post-Treatment Period.

Arms: arm 1: Placebo matching solution injected subcutaneously (SC) once weekly for up to 6 weeks and an additional loading dose on Day 3. arm 2: ISIS 757456 80 mg injected SC once weekly for up to 6 weeks and an additional loading dose of 80 mg on Day 3.
Interventions: intervention 1: Placebo intervention 2: ISIS 757456
Intervention descriptions: intervention 1: Placebo matching solution administered as SC injection. intervention 2: Administered as SC injection.

Protocol documents:
Prot_SAP_001.pdf: 
 
 
A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, 
Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor 
Administered Subcutaneously to Hypertensive Subjects With Controlled 
Blood Pressure   
NCT03714776  
14-November-2019 


    
   
        
  
            
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 


  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
   
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
             
                      
          
         
  
           
   
             
     


 
 
 
  
                     
 
 
              
 
       
                                
 
    
          
       
         
     
 
      
    
   
      
 
               
              
      
        
  
                  
     
 
 
                                  
 
 
 
       
  
           
    
             
  
 
               
             
                      
          
         
  
           
   
             
     


         
    
           
           
      
 
             
 
 
              
                  
 
             
 
       
                                
 
    
          
       
         
     
 
      
    
   
      
 
               
              
      
        
  
                  
     
 
       
     
            
      
       
 
       
  
  
           
    
             
  
 
               
                  
    
 
                
 
  
             
  
 
               
      
 
    
 
    
             
 
  
   
 
          
 
                  
                
           
         
       
                                    
          
       
          
          
                     
                                      
                                     
      
        
   
           
  
           
      
             
                      
          
         
  
           
   
             
     


         
    
           
           
      
 
             
 
 
                    
 
                            
       
    
       
            
                   
 
         
    
       
              
 
      
         
   
              
                   
          
  
  
           
    
       
   
           
    
             
 
                                      
                           
   
        
            
                   
 
              
      
              
 
      
             
              
          
        
        
  
     
           
                                 
                            
               
                                    
  
            
     
           
                      
                       
          
             
                                                  
      
        
  
             
           
       
 
 
 
  
 
  
   
         
 
  
 
   
   
            
 
 
  
                 
 
             
                      
          
         
  
           
   
             
     




         
    
           
           
      
 
             
 
 
  
                           
  
   
                 
  
   
      
  
   
       
  
   
 
 
       
  
  
   
 
     
  
 
                  
  
  
        
  
  
           
  
  
                
  
  
  
                 
       
  
 
               
  
  
   
    
   
  
  
   
    
    
  
 
                 
  
  
             
  
   
        
  
    
            
       
    
             
  
  
    
  
          
    
 
     
  
    
             
                   
    
  
   
          
  
   
           
  
   
            
  
   
 
 
                    
  
  
        
 
   
  
  
  
 
            
 
          
 
  
   
  
           
    
  
  
   
       
    
  
  
 
           
  
  
                
  
  
                    
  
  
                
   
  
             
                      
          
         
  
           
   
             
     


         
    
           
           
      
 
             
 
 
 
                     
  
  
            
    
  
  
            
        
  
  
            
                   
  
  
               
  
  
        
        
  
   
        
                 
    
  
  
   
        
            
    
  
   
        
                
    
  
   
        
                      
 
  
   
        
      
              
  
  
  
           
  
   
                     
         
  
   
                          
    
  
  
   
                         
  
  
   
               
    
  
   
                   
    
  
  
  
                              
  
  
                     
  
  
             
                     
  
   
     
                       
  
    
     
           
  
     
           
           
  
     
            
           
  
    
     
            
  
   
                
  
 
                                            
  
  
                          
  
  
           
    
  
  
  
  
    
  
   
   
        
  
   
   
                                       
              
  
             
                      
          
         
  
           
   
             
     


         
    
           
           
      
 
             
 
 
   
        
            
  
   
   
                  
  
  
  
   
                   
      
  
  
   
        
      
  
  
   
           
      
  
  
   
             
      
                 
  
  
    
                     
  
    
   
   
  
    
           
            
  
    
                 
        
  
    
               
        
  
    
            
        
  
  
                       
      
  
   
     
              
  
  
   
                                                 
  
  
   
 
    
 
  
  
   
  
                     
  
  
                       
  
   
 
      
  
 
   
        
  
   
  
            
  
   
        
 
  
   
                  
  
  
    
                         
   
  
    
        
  
  
    
         
  
  
    
               
  
  
    
              
  
  
                                 
  
   
            
  
   
                      
  
             
                      
          
         
  
           
   
             
     


         
    
           
           
      
 
             
 
 
    
 
                
  
   
        
    
   
  
  
  
                              
  
   
             
  
  
   
             
  
   
                          
  
   
        
    
  
   
         
  
   
                
  
  
           
  
  
          
  
        
 
                       
  
        
 
                           
  
        
 
                    
  
        
 
                                          
                       
  
 
 
              
      
      
   
       
                
  
      
  
         
    
 
     
  
      
              
   
  
      
          
           
  
      
  
               
                             
        
 
  
      
          
  
                 
  
 
 
 
 
             
                      
          
         
  
           
   
             
     


         
    
           
           
      
             
                   
               
             
       
   
       
            
                   
 
    
         
       
              
 
    
 
             
              
             
     
        
  
     
            
   
                 
  
              
             
                                                     
                
                             
        
            
   
                      
            
   
              
    
  
            
    
       
                                         
       
             
             
                          
                                        
         
    
                          
       
                 
                                                      
                        
    
                               
  
 
        
       
                        
 
             
    
             
       
    
      
   
                   
           
   
    
   
 
                  
      
             
                            
   
  
 
                        
             
                            
            
     
  
     
            
    
     
   
                   
            
   
    
   
 
 
          
   
  
 
 
          
            
     
  
     
            
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
             
    
             
       
    
      
   
                   
 
           
   
    
   
                      
                    
                
                  
           
 
                               
                          
             
        
 
   
  
                      
                    
                
                  
           
 
  
             
  
                  
  
  
               
  
                  
  
   
               
  
   
     
           
 
  
                  
 
  
                     
  
                  
  
                   
  
   
                    
  
   
             
 
  
                        
   
     
                
                   
       
     
  
     
            
    
      
   
                   
 
            
   
    
   
   
            
                          
    
                         
             
  
             
    
    
    
      
   
                   
 
           
   
    
    
                         
    
 
   
  
              
                     
    
 
  
              
   
   
       
                
              
     
       
    
      
   
                   
 
            
   
    
 
            
            
   
       
   
                                         
   
      
            
   
           
                   
        
 
   
  
                                        
   
      
            
   
                        
     
                                    
              
    
    
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
              
    
             
       
    
      
    
          
        
 
           
    
    
   
   
         
        
         
      
        
 
    
                                     
     
 
   
  
   
         
        
         
      
        
 
    
                                     
     
 
              
           
    
                
  
    
      
    
          
        
 
           
    
    
   
    
                
               
 
   
  
    
                
                   
                        
       
          
          
           
 
          
 
   
          
              
    
    
                   
   
                 
                     
  
              
                       
 
   
  
                 
            
          
                  
              
     
                 
                
         
 
         
         
                
      
       
    
 
             
 
   
      
    
  
  
         
           
                       
                                     
  
                                 
    
  
      
                    
  
           
             
 
   
  
      
    
  
  
         
           
                       
                                     
  
                                 
    
  
      
                    
  
           
             
  
                                 
 
              
                   
          
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
              
    
             
       
             
   
      
   
 
     
 
       
  
   
     
    
 
     
   
           
                        
          
        
             
  
            
    
               
   
            
  
         
    
            
    
              
                 
           
                                               
                     
 
   
  
           
                         
          
        
             
  
            
   
                      
        
                
        
   
           
  
         
    
            
    
              
                
           
                                               
                         
        
          
            
              
    
    
                  
      
           
       
    
   
                        
                   
                                                  
                     
               
      
 
   
     
  
 
  
          
     
                          
              
  
                                              
               
 
   
  
                               
              
                                              
                              
             
 
       
 
   
     
  
 
  
          
   
                                    
          
    
                                        
                     
 
            
   
             
      
                  
     
    
       
     
                                 
                
     
                     
   
    
        
 
   
  
        
             
     
                  
        
    
    
   
               
      
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
             
    
             
       
               
 
   
  
   
                                      
    
                               
       
  
   
   
    
                               
 
              
         
        
  
 
   
  
                                      
    
                               
       
  
   
   
    
                               
 
              
         
        
        
      
                                  
                      
         
      
     
       
                                      
                                        
                                          
         
    
      
              
       
 
      
                
                
 
              
   
  
                 
                      
                
                    
                    
          
      
              
   
    
  
   
     
  
       
                  
      
 
   
                   
 
   
  
     
  
       
             
             
    
                   
 
            
               
   
         
  
     
   
                 
                            
     
                     
           
    
          
            
             
                 
                  
        
                        
 
                    
         
     
              
    
  
                                         
     
              
    
        
          
              
                 
          
        
               
    
    
                
               
     
                    
         
 
   
  
                 
                             
     
                     
           
    
          
            
           
  
  
                 
                    
                                          
 
                  
                       
         
 
                            
     
              
    
               
                                   
      
       
    
                   
     
         
            
         
    
 
                           
    
           
      
     
        
        
             
         
      
                      
  
                 
 
    
              
    
    
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
              
    
             
       
              
   
          
      
    
   
                                                
 
        
        
                       
              
                                 
                
       
                   
        
                              
 
  
       
                 
   
           
     
       
      
 
                      
            
         
               
           
          
          
        
              
    
                 
               
  
    
        
               
       
                      
         
           
       
 
   
  
                                               
 
        
        
            
        
      
           
         
                
       
                       
                     
            
              
              
 
                                        
              
                            
   
       
                            
    
                         
   
       
 
                
   
  
         
    
               
    
                   
                                          
             
       
                      
 
         
     
                         
                   
                          
     
                
                 
     
                  
          
            
                                
      
             
    
        
             
  
                               
           
                      
              
     
        
                                
                         
                 
           
                   
   
   
          
                              
     
         
                  
     
               
          
     
    
 
       
          
                       
   
                         
          
      
      
    
                               
                   
                       
  
       
                      
       
   
          
      
                      
 
                
     
                      
             
  
                      
          
     
  
                   
                 
   
              
    
        
            
  
                              
         
   
                    
              
     
        
                              
      
       
   
                     
               
 
     
          
 
                 
    
          
         
  
               
   
         
 
 
           
        
                    
  
            
     
              
                   
 
                       
            
   
               
                   
     
            
                      
                  
                 
             
    
     
       
     
              
   
                  
 
 
               
            
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
              
    
             
       
                
                 
     
  
   
                     
                  
     
             
                       
       
                      
   
    
    
          
         
     
     
     
      
            
        
        
                        
  
                          
                 
       
    
                     
      
        
                          
      
 
   
  
                     
                  
     
             
                       
       
                      
   
  
                                     
     
   
  
                                
                          
                 
       
    
                     
      
        
                          
        
    
              
         
            
       
                              
   
                                 
        
   
    
                        
   
              
    
    
                 
               
  
  
               
                          
              
                 
  
  
         
                           
 
  
                   
             
   
      
 
  
      
                         
 
          
                      
    
        
 
                            
              
    
               
   
      
                 
        
    
   
         
            
                
                                  
    
  
                      
                 
  
                              
  
               
           
     
        
              
           
        
 
   
  
         
            
                
                                  
    
  
                      
                 
  
               
 
            
 
           
    
                 
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
              
    
             
       
                 
            
    
   
   
                             
       
   
     
           
           
       
          
   
                 
    
                 
                       
                        
               
          
                             
 
             
            
      
        
     
              
             
                                   
 
                      
                 
                 
                   
 
      
               
  
 
        
         
             
 
               
      
 
     
       
                 
  
        
           
             
                              
   
 
                                   
                                  
     
            
                      
    
     
        
                   
     
          
                  
    
   
     
      
         
                
              
         
                      
                                           
 
                 
      
       
                            
      
     
   
          
                  
         
 
   
  
   
                             
       
   
     
           
            
       
          
   
                       
   
                                      
                                     
    
                     
                     
          
             
            
    
  
              
             
    
                              
       
         
                      
        
                
            
 
   
                 
 
     
       
 
                   
        
     
      
                                 
                   
                  
       
                              
 
         
     
 
             
                    
                  
 
   
             
         
 
   
   
     
             
        
      
              
    
             
              
  
           
    
          
    
        
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
              
    
             
       
                 
            
   
        
   
          
   
 
                                         
                       
                
  
                     
          
     
                     
               
 
                 
    
         
    
          
                             
         
                        
   
          
                            
                                          
                    
                
  
      
       
                   
        
      
         
          
   
                       
 
             
                    
                  
 
   
             
         
 
   
    
     
            
        
      
              
                 
              
  
           
    
          
   
        
            
            
   
       
   
             
            
        
  
  
                                   
                                         
    
                 
    
    
     
              
        
 
   
  
             
            
        
  
  
                                   
                                          
    
                 
    
    
     
              
            
        
        
 
              
 
                 
           
  
 
          
 
 
             
              
    
   
      
                              
     
   
      
            
   
                  
                          
         
   
   
         
                        
               
 
   
  
      
                              
     
   
      
            
                       
                          
         
  
   
         
                        
                   
            
      
     
                 
                           
          
                                  
                  
                
    
                    
        
               
       
                       
              
 
         
 
      
                   
        
 
          
   
              
     
         
        
  
     
  
    
  
   
                
    
       
           
                   
               
          
   
              
                  
                
    
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                 
       
   
       
            
                   
 
         
    
       
              
 
      
             
    
         
                   
        
  
     
         
 
    
          
       
        
     
    
              
             
                                          
     
            
      
                 
             
                    
    
          
          
               
            
            
                        
                          
                  
               
                               
               
            
 
            
                       
                    
             
  
          
  
                      
            
 
     
       
         
       
                                                       
                         
                           
             
             
        
  
        
    
                        
      
                 
      
    
     
            
      
          
                
                
  
            
         
    
   
          
    
            
               
                      
   
        
                                 
        
   
    
 
                     
     
                                
            
    
            
       
    
        
                            
          
              
     
            
                              
    
                                         
    
               
                                   
             
     
                              
 
   
                            
         
                        
   
  
          
                        
       
                     
               
           
     
               
    
                  
    
           
        
                                
                                 
     
           
    
                                   
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                    
      
         
      
       
   
            
      
       
                                
             
             
                              
      
                            
            
         
   
                     
       
                     
          
        
   
            
          
                 
        
                  
            
     
  
         
 
    
          
 
   
         
                                        
  
          
                    
   
          
               
       
              
   
                   
                       
                
   
                   
                                    
   
                               
            
          
     
      
                  
            
          
        
                          
                
           
 
  
            
   
                      
   
                   
   
                    
    
                  
   
                     
   
                     
   
                     
                      
    
                    
   
                      
   
                   
   
                     
   
     
                        
             
     
               
   
               
                                  
 
   
 
      
                      
     
                  
   
                
            
         
          
         
 
   
                  
                                       
           
 
   
       
                       
     
 
          
         
                      
                         
         
       
               
          
                                      
     
      
       
             
                                    
     
   
    
  
 
                           
            
                           
       
  
        
  
                                     
              
             
                
        
                
    
      
           
    
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                    
      
         
      
       
   
           
   
     
  
          
           
                  
              
                             
          
                     
 
      
             
     
      
               
            
                 
            
              
                   
    
         
      
    
  
         
    
 
                  
     
              
    
                            
 
                                
               
          
                    
                                        
         
            
                                 
              
                                             
 
               
   
              
                               
     
     
          
     
 
 
                  
  
   
                       
                            
             
         
                
                  
   
        
            
 
 
   
    
     
       
   
   
       
                                      
          
               
                            
   
            
                                         
     
                                     
   
                   
                
         
         
    
                       
 
 
   
               
    
            
        
                                      
                
                          
          
    
  
     
                                     
        
                        
      
        
      
           
                              
                     
                                     
  
                         
          
          
    
          
          
         
                                     
          
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                    
      
         
      
       
   
            
      
     
                      
           
   
   
    
          
                  
  
 
 
   
    
           
       
                
      
              
                  
            
   
               
                
      
    
     
         
        
                    
            
            
                              
   
         
  
          
       
     
       
   
    
                
                             
                 
    
       
                       
 
              
                
                      
             
            
         
  
                  
           
                        
      
         
            
              
             
      
                              
                    
      
                 
  
    
     
                                           
            
   
   
                                                  
      
          
            
             
       
                                 
   
 
    
                        
   
                 
 
    
    
            
     
   
                 
              
                
   
         
  
              
  
     
          
           
                      
         
             
             
   
                
             
   
       
                
   
            
               
                 
 
                   
                              
         
  
          
          
                      
   
   
                                    
       
                     
                  
  
                              
                                
                    
                    
  
                         
            
                             
            
    
     
       
                          
      
            
                         
       
      
 
            
    
               
        
    
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                    
      
              
                
  
    
 
                         
     
                
                                        
                            
                   
   
  
    
                               
              
                 
               
                                              
              
                 
             
      
         
                                                 
                   
       
  
 
 
     
                        
                                       
               
                        
         
         
                                      
                                                     
   
        
             
                    
                                       
     
                          
                            
      
        
 
    
    
   
                 
                    
                            
  
          
                
  
                        
          
            
     
 
        
                       
                          
            
     
        
       
                                               
    
 
                  
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                    
      
     
                       
  
      
      
                    
                      
  
    
 
                       
     
                
                                        
                                   
  
                         
                                        
  
       
         
   
                                             
    
     
                                    
              
       
  
 
       
                    
    
                                  
                   
                               
  
                          
              
                         
                                    
                 
               
  
           
                                 
       
  
                                    
                      
          
       
   
          
  
               
         
          
      
             
     
        
  
         
              
          
        
 
   
                
               
  
  
                                                           
 
       
  
  
                               
  
                   
   
            
       
       
         
        
                      
       
  
  
              
              
     
                      
                         
  
              
             
           
           
      
    
  
 
   
    
                
     
           
  
 
                                                  
 
       
          
      
  
                        
      
                 
                    
     
                   
     
                                   
         
    
          
  
                      
  
                     
     
     
               
      
                        
 
      
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                    
      
 
      
    
    
 
 
 
                   
  
    
 
           
         
        
                
                 
                                                              
       
    
     
         
  
            
                     
                                       
                       
                          
               
                               
          
                        
              
           
         
       
  
          
        
 
 
             
                      
          
         
  
           
   
             
      




         
    
           
           
      
 
             
 
 
 
               
      
     
  
    
      
   
        
  
   
            
    
     
      
           
    
     
      
                
   
   
        
    
     
       
    
               
    
         
  
          
     
        
         
      
    
     
             
   
    
             
       
                   
    
 
                
    
                 
     
                   
          
              
  
   
           
 
  
      
       
   
      
    
    
      
       
    
    
         
      
   
            
     
    
            
     
    
        
   
    
           
    
            
   
                 
       
                
         
      
   
    
 
          
    
    
            
     
              
      
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
 
  
              
     
            
        
    
 
   
             
       
                
    
                
    
   
       
      
   
     
          
    
   
       
    
   
       
     
   
    
   
                   
   
   
       
  
   
  
  
      
                   
    
    
    
     
    
   
                              
   
             
   
                   
   
 
                
   
                        
  
 
      
  
    
                   
    
     
         
 
         
    
                      
      
                           
     
    
                   
     
   
                         
    
   
     
   
     
      
           
   
                     
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
      
 
                  
    
        
            
    
        
  
    
     
  
           
            
       
      
   
         
      
            
       
        
                                           
     
     
  
   
           
   
            
  
   
                                
   
          
  
    
                 
      
                
  
   
           
      
   
     
    
      
    
      
 
         
   
         
                          
                   
      
         
   
   
    
   
  
       
    
        
        
    
 
       
      
    
 
          
    
     
     
                 
   
         
   
            
          
                         
               
          
                   
       
                         
         
      
     
          
        
   
                     
      
         
          
    
     
         
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
     
        
           
    
            
   
      
       
                       
 
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
   
                       
    
       
     
              
                
                                          
     
            
     
     
                 
                
                    
    
          
            
            
 
            
     
            
                           
               
          
     
                 
                
                               
               
            
 
            
                        
  
                 
             
  
         
  
                      
            
 
     
       
         
       
                                                            
                     
                                     
   
             
        
  
        
    
                         
                     
 
    
          
  
     
            
  
                            
                                    
                 
     
               
  
              
                                 
       
  
                                       
                      
          
       
  
     
          
  
                  
         
          
      
             
     
        
  
         
              
          
        
 
   
                 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
     
                 
                                                              
 
       
  
                                  
  
                      
 
          
       
       
             
                
              
       
  
                 
              
     
                  
                             
                 
             
           
           
           
   
 
   
    
               
     
           
  
       
                   
                           
       
 
        
      
           
               
      
                            
          
     
                         
                
                  
         
               
                         
  
                      
     
     
               
      
                          
      
   
                        
    
          
     
 
         
                                     
            
             
                                                     
                               
           
 
           
               
             
                                     
              
      
                                               
 
                   
                                       
         
          
                                 
                      
         
               
                
       
           
       
                  
  
           
     
      
 
    
       
          
         
    
      
           
        
  
               
                                                     
       
  
           
                 
                         
 
           
                                
 
                           
       
       
    
                                              
            
           
       
      
         
   
                            
    
                             
                          
 
  
                                                             
           
             
                      
          
         
  
           
   
             
      




         
    
           
           
      
 
             
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
    
   
 
   
 
     
     
   
  
 
     
    
                      
                  
                 
    
      
  
               
                                             
            
  
                                  
        
     
    
         
          
            
    
         
          
             
   
                       
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
   
    
             
    
          
 
  
                   
                     
                    
           
        
       
          
              
          
   
                       
    
         
  
    
 
                    
              
               
                                     
            
                        
            
                 
      
                                            
                        
     
  
                   
 
                   
 
           
           
 
                  
                    
              
 
                        
       
                            
    
    
  
             
                         
                    
                         
                                       
                    
       
 
    
                    
 
      
                 
       
                
    
             
  
                
                         
        
                          
        
 
            
       
            
                                                   
               
     
                                                                 
    
          
              
 
                    
                
    
                          
   
        
    
                            
                    
                                
                     
   
        
                                   
        
                        
                              
 
 
                    
    
           
             
     
       
         
             
         
       
                   
        
    
               
                              
        
   
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
     
                  
        
            
             
           
          
     
   
                                  
                             
    
 
                              
  
          
           
       
   
   
         
    
        
           
            
          
   
        
     
 
     
     
      
   
                     
  
                       
   
      
          
                                               
  
    
                 
     
        
        
  
    
 
                                   
              
                                             
  
                       
                                                                    
    
                          
     
 
         
    
                                  
                         
                        
   
                        
 
    
   
 
     
       
 
                          
  
       
         
   
                   
    
         
        
                                    
                       
  
    
                                                         
                                 
    
   
                                 
    
 
   
      
        
                       
       
                          
     
       
                                                                
 
                              
  
     
                  
   
              
        
             
                     
      
 
                                                                 
        
             
         
                
  
           
    
             
          
       
      
         
    
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
    
       
     
    
  
                                      
 
   
       
                                          
         
                  
   
                                                         
      
                       
                   
                     
   
           
        
  
    
 
                                   
           
              
               
                       
  
             
                                 
                  
        
   
        
              
                  
                              
   
                  
      
                    
      
              
                            
  
 
    
                
  
    
      
                                                    
       
         
    
  
                
       
                   
     
                 
      
                  
                           
               
                     
                                         
       
              
                         
     
           
                   
                 
                  
                  
      
    
                             
        
                              
                            
   
                  
            
    
                       
                            
                
                                                                     
                                    
                            
               
            
 
   
 
   
          
      
              
        
               
                 
   
   
                                        
                  
   
    
   
    
   
          
    
            
               
                          
     
   
                                 
           
    
 
                     
     
                                      
      
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
    
            
       
   
        
                            
         
             
     
                      
                   
   
                                         
           
       
                        
                    
    
     
                               
   
      
             
        
                                  
     
          
  
                     
                
           
                                
           
    
    
                  
     
           
        
       
                                                       
 
     
                
                                    
       
      
   
                      
                   
       
                             
                
                 
            
             
           
          
       
                                
       
   
      
      
          
               
             
             
           
     
  
         
 
    
          
 
            
                                       
  
          
                    
   
          
               
       
              
                      
                       
                
                      
                                    
   
                      
         
            
          
     
      
                  
            
               
   
                          
                            
  
             
  
                    
  
                 
  
                  
   
                
   
               
   
   
               
   
                      
                    
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
   
                  
   
                    
   
             
   
                       
        
                       
             
     
               
       
           
                                 
 
   
       
   
                  
     
          
        
   
               
            
         
          
         
     
   
               
                                              
  
 
   
       
                      
     
             
  
      
                      
                         
         
       
               
          
                                     
     
      
              
       
                                    
             
  
 
   
                       
           
                           
       
  
         
  
                                    
              
           
                
                        
         
 
           
   
    
   
          
   
     
  
          
           
                        
        
                             
                   
             
 
      
            
     
      
               
            
                      
       
              
                   
    
         
      
    
  
         
    
 
                      
              
    
                            
  
                                
               
          
                    
                                        
         
            
                                 
                      
                                    
                 
   
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
              
                              
          
 
        
     
   
                  
  
   
                       
      
                          
       
         
               
                  
         
 
            
 
  
   
    
     
       
   
          
                                      
            
                   
                       
               
                                             
                                     
                     
 
                
         
          
    
                       
 
     
    
         
    
            
        
                                           
          
                          
                
     
   
                                 
                             
   
      
        
      
                                    
     
   
                
                                        
 
                        
          
          
              
         
         
                                                 
    
                      
           
   
       
          
                  
   
 
       
           
      
                
                
   
                  
            
                  
                
     
    
          
    
        
                    
                         
     
                        
            
  
          
       
     
       
       
                
                             
                 
    
       
                      
       
        
                
                      
             
            
           
   
             
                                           
       
            
              
                   
 
                             
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                    
      
                   
          
  
                                                     
   
   
                                                        
 
         
            
            
        
        
                        
    
    
                       
   
                  
    
 
  
            
     
   
                                
    
            
            
  
       
           
  
     
          
           
                      
                      
 
           
                     
             
          
               
  
            
               
                 
 
      
            
                              
           
          
          
                      
   
   
                                   
       
                    
                
  
                             
                                 
   
                
                   
  
                         
                 
                        
            
    
            
      
                   
     
            
                                
       
  
          
    
               
        
     
   
                 
    
             
    
                    
                                         
                   
   
         
   
                              
            
                                       
              
                                
 
                     
     
 
   
  
                                                
   
   
    
             
              
  
          
    
 
   
 
                             
                   
    
                    
                              
           
    
                        
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
     
         
                         
            
         
             
   
                        
                                  
               
 
   
                     
                    
        
 
            
                            
     
        
                       
 
                       
  
                 
                    
    
     
        
                        
  
  
         
   
 
                                 
                            
    
    
  
                              
       
   
        
    
       
                            
      
        
                                              
            
               
                         
        
            
                      
   
                
      
             
             
               
 
      
    
  
                              
 
                         
   
                                                        
           
                   
 
             
   
            
       
    
          
 
       
                                  
             
      
    
  
   
         
           
                                           
                 
                                    
    
   
      
                    
  
                         
                                  
     
  
   
            
                 
            
                
              
         
          
    
      
    
    
    
                   
       
                             
      
   
 
          
     
 
     
   
  
       
 
     
                           
         
      
    
 
                           
                                      
 
      
                      
                        
                 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
 
             
  
            
                              
       
              
   
    
  
         
    
                 
              
             
  
 
                                                               
      
      
           
  
         
    
                 
    
          
               
 
                                          
                
                            
                       
        
  
            
          
  
          
                      
           
        
   
 
        
    
 
     
 
     
       
     
       
 
    
       
        
      
         
                 
        
                
      
         
       
 
    
                            
 
      
              
                    
      
    
  
            
             
       
  
       
                 
                                                                  
        
                                                        
       
                                       
                      
                             
       
       
       
 
   
     
  
 
  
          
                                       
             
                                                               
       
 
                               
    
                         
  
    
  
             
          
         
       
              
   
                
                           
     
       
          
     
            
               
                   
  
         
                        
                      
     
 
               
             
   
      
       
                         
                               
  
   
    
       
                 
     
            
            
                   
  
                               
                        
                                          
      
      
                                
                   
  
                     
 
   
          
                                
 
   
  
                  
     
  
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                   
       
                                              
         
   
    
       
                   
     
              
        
  
        
                                             
 
     
              
                                                 
            
            
                
      
        
       
         
                                                       
  
    
 
                                                             
                            
            
                     
   
            
 
     
  
                      
                  
 
                 
              
                
            
    
                  
                
                    
            
     
    
  
                             
     
                      
    
                                 
      
                           
 
                          
 
                        
     
 
             
          
      
                    
                      
       
     
                       
                                              
                     
 
   
    
    
  
                             
     
        
 
             
 
                                
                  
              
                
            
    
                  
                
                    
             
  
    
          
 
   
   
                   
                             
              
                              
                           
         
 
    
    
    
                 
                                       
 
                                    
                                      
                       
           
       
      
   
    
                              
 
              
         
        
              
                 
                                     
              
               
                                                                     
                                  
                  
    
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
    
 
            
 
          
  
     
       
            
  
         
   
  
                              
    
          
        
                                            
     
              
                    
          
                      
                                
      
          
        
                                      
 
                   
  
                  
              
                                                
                                             
  
  
    
                                   
                   
       
                
                         
     
       
                            
        
                   
              
                                  
     
      
        
    
   
        
                          
        
                   
  
          
  
   
     
            
                        
              
   
                  
                                  
        
                         
          
  
      
                
          
      
         
                                       
           
              
           
       
             
       
         
   
         
                     
             
       
       
     
                     
                  
                      
         
                 
      
         
    
      
           
      
   
                      
                     
      
                             
                       
           
            
             
                     
       
                                
       
                                                                
                  
                     
  
    
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
     
             
  
    
   
  
      
          
               
             
             
           
     
  
        
  
     
  
       
      
       
      
       
    
    
        
       
   
           
    
              
    
                                 
     
             
                                                       
   
           
                          
                   
      
               
             
                                       
                
     
                       
        
                 
   
          
          
       
      
           
           
              
                    
                  
          
      
   
   
 
    
                    
          
             
     
                                       
                   
     
      
            
    
   
    
                 
   
        
     
                      
   
            
            
                                                              
 
                      
   
            
   
                      
    
             
  
    
       
             
                          
                  
     
               
            
     
                           
        
                                                    
     
   
                                                                
      
                                                    
    
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
        
           
            
           
     
        
        
               
 
    
           
             
                       
            
    
                
    
           
                          
                       
                   
    
             
    
                           
    
    
       
          
        
                    
   
                        
   
 
       
     
                  
                    
                    
               
                 
                               
      
  
  
                         
                      
 
          
 
    
                
                  
    
                
 
     
         
             
                                   
 
          
              
   
                                       
   
         
               
                           
  
                    
                       
         
   
    
       
        
                                              
   
                 
  
    
          
                           
 
             
       
   
                        
                  
                     
              
                 
           
                       
       
     
                         
  
            
                   
                     
          
                                               
             
            
          
                                         
   
                        
                             
    
  
     
          
                         
            
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
     
       
                     
      
 
                                            
                  
               
             
                                       
                      
               
                                                           
           
           
               
          
            
      
                
       
             
       
       
            
      
                  
                        
       
  
     
                 
           
                    
   
                                   
       
      
       
             
                
                    
 
      
                
        
           
     
              
   
                                           
                    
          
      
           
    
     
        
    
           
                                  
 
                            
                             
       
  
          
                  
                  
         
            
      
       
                          
 
   
 
     
      
               
                        
                      
  
  
               
          
                        
       
                                            
    
          
       
    
             
               
                           
   
                             
            
                 
      
        
     
       
               
    
                 
                                 
                 
   
 
                
          
            
          
  
  
                
                                             
                 
                  
                               
                               
     
             
    
  
                                              
              
  
 
                   
              
          
            
 
                           
    
                             
    
  
                       
     
                           
 
               
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
     
       
                    
     
                                                   
          
     
  
           
        
                  
        
            
  
                              
         
                
     
             
             
                              
                        
                               
       
                            
                     
      
           
                 
   
           
    
       
                
         
  
         
    
 
    
          
                           
            
           
                                                
   
    
 
           
                
  
     
             
             
            
      
                    
   
 
     
                 
   
                      
 
 
     
      
  
         
    
 
                               
                               
                 
  
      
                                 
       
  
  
         
    
                
                                             
      
                        
      
    
                
 
         
         
   
                       
 
                                     
    
                     
                
           
          
          
        
                  
     
           
                  
             
            
  
                              
         
                 
     
             
             
                              
                        
                            
     
            
      
       
                            
     
         
          
                                 
 
  
            
          
                          
        
                                   
                      
                                                   
   
   
    
                
           
         
                              
                      
            
         
               
                      
          
   
                      
                 
               
  
    
        
               
                             
         
                      
             
        
    
 
                                                     
       
                    
                 
      
       
     
                      
        
    
            
          
 
                       
                                      
      
                                        
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
     
       
                         
  
          
               
             
                           
  
          
                         
                          
  
  
         
                
            
           
   
     
     
 
          
                                                   
      
             
                                          
      
        
                   
                                        
                
               
                                
    
              
             
                
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
        
  
                                              
        
 
                          
                                              
             
 
       
      
     
               
                           
                 
               
         
    
                                  
 
                 
 
       
    
           
        
                  
                             
     
       
  
          
                   
      
    
    
         
           
         
  
               
           
             
  
     
       
                     
     
  
                        
    
             
     
                            
          
 
       
   
                               
 
     
       
         
               
  
              
                  
     
                  
              
              
                                     
   
   
                                                         
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
   
    
      
                    
                               
    
      
    
            
                                       
   
                                
                       
 
   
             
       
      
   
               
                                 
 
   
             
       
      
     
                      
       
    
                     
   
             
                 
       
    
         
      
  
    
                     
     
            
                               
                                 
  
                 
    
            
              
    
                               
     
                               
          
             
                               
             
                        
                               
                          
      
       
                          
                 
           
                  
                   
     
    
         
     
                           
    
   
                     
   
               
     
             
  
                            
                    
     
                                                          
                               
                       
     
                                         
     
         
                    
                          
                        
    
    
                
           
 
   
                           
      
      
             
        
                                      
             
                     
                    
       
  
                 
   
     
                          
  
                           
            
     
                 
        
     
                               
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
        
           
  
                
  
     
          
 
     
     
  
       
        
  
    
   
  
           
        
   
      
   
            
            
           
      
            
     
      
   
  
        
               
       
   
                  
                 
 
                 
  
      
                        
   
                            
        
                          
               
            
         
              
                     
          
                           
                         
       
 
               
            
          
             
               
    
  
      
  
 
      
                  
        
   
      
 
        
        
       
               
           
            
            
             
   
   
  
        
               
       
   
                  
                 
 
                 
  
        
                   
       
    
                           
           
  
 
      
                  
        
  
        
        
          
             
   
   
  
          
       
              
      
                        
 
      
                     
      
            
                 
  
   
                        
 
                     
  
 
      
                  
        
  
        
        
          
             
   
   
  
          
       
              
      
                         
 
      
                     
      
            
                 
  
                               
 
         
  
   
         
 
             
          
     
  
 
      
                  
                                      
                                              
              
               
     
 
                                  
       
                       
    
               
            
            
       
      
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
  
                     
                          
                   
                       
                     
       
     
 
          
      
                 
        
  
                
   
                          
 
           
                    
   
                                                    
         
  
  
      
     
                         
  
              
                                                
                                                             
                               
  
      
               
  
              
                  
     
                  
              
              
                          
   
   
                                  
     
                
    
               
       
                                      
      
    
                    
    
              
             
           
                                                              
                              
       
  
        
               
  
            
                                                 
   
                         
                    
                  
   
           
                          
   
     
           
   
                 
                    
     
                 
              
                           
     
                     
     
                                
       
         
   
      
 
  
       
                 
   
                       
   
                                                                 
          
                         
                     
          
             
           
      
             
 
            
                                   
         
      
                      
                        
    
         
 
                     
 
     
       
            
        
        
                                         
                  
     
                                 
   
                      
                       
               
     
          
 
            
           
                 
                     
               
                            
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                      
                        
      
   
                 
           
      
    
                                                     
           
                  
                       
         
        
                  
                
                
  
    
        
               
                             
         
                      
            
             
 
                                                             
           
                  
      
       
              
             
      
         
          
                  
               
   
            
          
                      
   
                                            
             
                          
    
  
                                 
          
    
  
         
                                       
  
                      
                          
      
    
   
   
                 
        
        
   
                                   
            
    
        
                                 
            
                
     
                          
       
                           
                           
                                 
                   
         
    
        
       
           
                            
                           
   
                               
      
  
                      
                    
 
              
                                                          
      
                       
                 
                
    
              
                        
    
   
     
                                       
   
               
               
                    
            
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
           
            
                           
   
     
             
                  
   
     
             
                           
   
  
                  
  
 
  
                         
                          
        
          
        
                         
               
    
                 
             
    
           
               
               
   
                                                
                   
                                                                  
                          
                  
                
      
  
                      
                    
 
              
                                                          
      
             
     
     
                          
              
                                
                     
 
         
      
            
                            
  
     
                    
         
      
     
            
       
                  
        
           
                  
            
                              
     
           
             
                     
       
           
            
                          
            
                       
     
    
            
         
     
                      
      
      
                         
 
 
                   
       
                      
             
  
      
                       
      
       
            
            
             
            
        
  
                                                        
                          
                 
    
 
   
                   
           
 
        
    
                  
                          
          
 
              
 
 
                  
  
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
   
                       
      
                           
             
               
                  
   
        
            
 
 
   
    
     
       
   
      
     
              
       
                                               
         
      
   
 
                                  
   
             
                         
                     
     
           
      
         
          
                                                  
 
 
   
  
              
                             
    
                            
            
                                              
        
          
               
        
                                     
  
    
                 
  
               
               
          
           
   
   
        
      
    
                                 
        
     
                                                       
           
     
            
    
  
                       
      
   
                     
 
                  
  
      
                               
      
   
             
      
                                
                 
                  
 
                                               
            
       
              
    
     
                 
    
                             
   
              
    
                                          
                                 
    
            
   
           
     
                       
          
                           
     
                                                   
            
   
 
       
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
    
  
    
     
            
      
                                                               
                              
            
       
          
         
                                 
                      
   
            
                                  
                                                            
         
            
       
                         
             
                             
           
                       
    
        
                 
             
                
   
      
             
             
                         
      
                                          
                 
       
       
                                      
   
         
                     
      
      
                                                
         
     
                               
           
         
 
  
     
                                                            
                       
                            
                       
          
 
                     
                   
  
                    
  
                                                               
     
         
           
  
                                                                 
                                                        
           
 
 
                               
                                      
                                             
                
    
  
                              
   
                              
   
            
            
               
                         
             
  
      
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
     
                      
                                     
               
          
       
   
     
         
   
 
             
               
                            
                  
            
      
           
            
         
            
     
                           
  
                                        
                     
   
                                    
      
                                
             
                        
                    
           
  
                     
          
     
       
       
                
     
            
  
              
        
     
                       
             
 
             
                          
      
             
                           
              
     
                
        
                        
    
                                                   
  
                                            
      
 
  
                           
                         
    
   
                                             
    
    
                                                     
                      
     
                                
      
    
         
          
          
                                         
          
         
         
      
         
                             
                     
                         
     
 
         
  
                          
                           
         
   
    
 
   
           
                       
 
                                
     
    
                   
   
              
                                      
              
                                     
                       
                    
                                    
            
        
                                     
                    
             
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
    
  
                             
  
       
       
                  
                               
    
                  
                         
                   
     
        
       
     
             
                          
     
                   
            
         
     
           
    
     
           
            
             
    
     
                
  
        
                         
           
    
       
     
                                   
                  
      
         
               
 
                                         
                                                              
 
   
                                               
        
      
             
                       
    
          
                 
   
    
                    
                
      
             
             
                  
           
                   
                                              
                 
   
 
                                    
      
                        
                            
                                                  
           
  
       
            
                           
      
          
 
                             
         
  
      
   
         
  
                     
                      
                      
    
    
                       
               
           
   
     
      
     
                   
  
                        
                                        
    
                       
                                        
               
     
                                         
                     
               
      
     
    
                
                   
  
      
   
                                              
           
   
      
      
  
                     
       
                                                  
                                                               
     
          
             
  
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
    
                                         
          
   
     
                                  
                
                               
     
    
                                                     
        
                              
  
             
                      
                    
           
                    
                     
           
       
           
                                                    
              
   
         
                                    
    
                 
                              
      
       
      
                              
         
      
            
  
                     
                          
         
      
 
        
                                            
         
 
      
                    
                                
  
                                                         
     
          
               
  
   
               
                               
           
 
          
   
                                      
   
 
       
  
         
 
          
   
                                          
        
       
     
    
            
   
                                    
  
     
            
   
     
          
      
           
             
          
                                                       
                                          
             
        
                  
     
                 
             
   
     
          
   
   
                   
                
     
                       
                   
          
   
                
    
                                     
 
                 
                 
                  
    
                       
       
                                
             
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
      
                            
                              
                                  
   
               
                    
                       
   
           
                       
   
      
                        
               
                  
                                    
        
                   
                    
                                            
              
                                                   
                                                           
 
             
                   
    
    
       
           
                            
                                   
                       
     
              
                                          
  
       
                                                    
                                                       
                                                                 
                            
             
                
     
         
                   
                                               
  
        
                     
     
                                                           
                             
                            
   
   
   
      
                     
   
             
 
                      
                       
                    
                          
 
                   
              
     
    
              
 
                             
          
                                       
                       
    
            
     
                             
                     
   
                
              
        
   
            
        
         
  
 
          
             
   
     
                                                      
       
                            
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
              
                                  
                                  
           
                                 
            
    
   
       
           
                               
            
         
          
           
                       
 
         
   
       
    
                
          
      
     
      
                
  
     
  
                   
    
                        
    
  
         
       
                                            
 
       
       
       
      
                                     
                              
                                 
      
            
         
                                      
  
     
  
          
   
                    
      
           
      
                
                              
              
                         
                  
  
              
   
                  
       
    
               
     
        
        
                                            
      
         
                                 
           
              
  
                   
                      
   
 
 
             
                                     
     
                                   
                    
  
                                              
       
          
     
                                             
                      
                                                         
                    
   
               
                  
 
         
               
          
         
                                        
                                       
         
            
       
                   
           
                     
                         
                                                             
                            
   
     
 
          
         
 
                               
     
 
         
                       
     
                                    
                               
      
                        
                 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
 
      
                        
           
                          
                             
                                  
     
                                     
                
                                                                    
                         
       
                    
           
                  
     
       
                 
       
           
                            
                  
           
      
 
                      
                      
                   
 
                 
  
                             
        
                            
   
   
             
   
                               
      
   
     
  
     
       
                  
       
   
                  
      
        
         
    
      
                                
                                                       
                 
          
   
                        
                       
   
                 
      
             
                
       
                                                 
        
      
                                   
    
         
  
              
     
 
                       
           
 
    
 
    
       
          
                           
                    
 
                                
                                
  
                   
       
                                        
   
   
                        
     
                   
       
                 
                                   
              
        
            
                                      
         
      
                  
                             
     
  
     
                      
    
    
                       
     
  
  
    
    
  
    
 
                                 
               
 
        
  
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
     
        
      
           
              
                     
           
                                                 
       
       
               
  
                  
         
                
                         
                   
             
                       
    
                         
                                       
   
                
 
   
  
          
     
                                                 
        
     
                                                            
  
                   
     
  
            
                     
                                                 
    
       
                                    
 
   
  
          
     
     
             
       
        
     
         
  
          
                        
              
                  
     
                  
  
                  
 
                                 
                
         
  
            
    
                                  
                   
                                         
       
         
      
    
      
                          
                     
                     
          
          
         
                
          
       
     
  
    
  
    
         
          
  
            
         
     
      
      
                            
   
                         
   
             
           
     
                             
                                    
  
    
              
     
        
                            
  
    
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
      
        
  
           
  
                            
                                         
                            
                                    
                           
             
                
       
          
    
      
                         
     
           
          
         
  
      
             
     
         
  
  
             
               
                                           
     
            
         
                                
                       
                  
    
  
             
        
                            
                         
  
                       
                    
                    
               
  
                                                   
                   
           
   
                    
                               
              
    
                    
                         
               
           
      
         
  
    
        
  
            
                                         
                                                                        
                     
             
       
                 
        
             
 
                           
                       
                 
   
            
             
       
     
  
    
        
       
            
            
      
          
            
         
 
           
       
                                                    
 
       
                                                     
            
       
                                     
       
     
   
                                                                      
      
                
  
                                                             
   
                                        
 
                
     
                   
                               
      
         
                         
                 
        
                                  
       
         
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
    
     
           
                                     
             
  
             
           
      
       
 
                 
  
                 
       
        
  
   
                                                          
             
      
                                             
 
                 
                          
     
                       
          
      
              
           
        
                                                      
      
                
                                                                
      
                                                         
       
   
     
  
                      
            
       
       
     
       
      
                                                          
                     
                 
            
        
  
                  
                    
        
              
     
             
           
                                               
     
    
  
       
  
                 
                              
                 
                             
                 
                
                      
              
     
                     
    
           
           
            
                   
                     
     
      
       
           
           
                                       
                                         
                      
    
                                  
     
              
    
                                                  
            
                          
    
                       
          
   
           
        
         
             
   
                        
                         
      
         
   
                                                
         
                                                
                
    
     
             
             
                
       
                             
                   
   
   
           
                                
                         
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                            
                                 
       
                        
  
          
 
        
   
       
         
                                         
   
                      
   
       
                                                            
    
 
     
                      
                               
         
                        
                                    
                           
    
 
 
             
     
 
 
                 
                                            
                   
              
           
       
              
                    
    
                                          
                       
                 
                                              
   
                  
    
      
                                   
 
                                          
                       
                
   
          
       
                           
 
      
      
    
                
                             
                      
                                          
   
           
                                          
          
      
          
    
                  
                             
   
                                 
               
      
     
        
                           
                 
                            
   
    
          
              
                    
                   
     
        
   
 
   
      
      
                     
    
                         
 
  
                  
    
                  
            
      
 
 
 
    
                           
                       
       
        
                                    
               
  
  
               
     
            
                      
                   
         
   
         
       
     
                                      
     
            
       
               
  
                 
 
                                  
       
                       
 
                                 
          
                     
            
                                                   
 
                         
    
                  
             
  
    
             
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
    
  
 
                             
     
              
  
             
   
              
      
                             
         
      
                             
            
      
                                    
           
              
       
             
                          
                    
       
                  
          
     
                            
                   
 
     
          
    
                                           
                 
           
                              
           
        
   
           
           
        
 
                          
                  
                 
     
            
               
                
          
                                    
           
      
      
                        
       
     
            
      
       
                                             
       
 
  
    
            
     
           
                             
         
                               
              
           
      
 
                       
             
              
                 
                    
  
      
                           
                       
       
  
     
    
                 
                            
  
                                                          
                  
        
             
        
                     
            
         
        
                  
   
    
                    
            
    
   
        
                                
                             
          
   
                                                        
             
                                  
        
                   
                     
          
     
      
                
     
     
             
                
               
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                        
      
     
   
                            
         
                 
     
     
                             
                        
     
   
          
  
     
       
      
                                 
       
        
                 
         
                             
               
        
                  
                   
                       
  
    
           
                   
                              
            
        
                              
                
              
                                                                       
   
                                                    
       
     
      
 
      
                    
                             
             
  
            
    
                          
           
             
                     
        
  
                        
                       
  
       
   
                        
           
                               
 
            
   
           
                  
                      
           
                            
    
  
             
                                        
      
        
                               
    
                
              
  
       
  
                 
              
           
           
                                              
    
                  
                  
                           
      
            
                                    
    
        
     
                                                 
              
        
                                             
                       
    
           
            
     
         
      
   
   
                 
                                       
        
          
                                  
          
     
  
                                               
      
   
    
                                   
     
     
      
            
                    
                         
 
      
     
                       
       
  
                              
   
       
                 
                                    
               
                   
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
    
           
       
        
                                
     
         
 
            
               
           
    
                  
       
    
                                     
                        
     
                  
     
   
              
        
   
   
  
    
                           
                         
     
                                
                             
                                                   
     
    
               
        
    
     
                    
      
 
               
                     
            
      
                         
                
       
        
       
               
                  
      
                
                                     
 
       
                                
             
        
      
   
            
                                     
                                   
         
      
                
                                  
         
     
                                         
    
   
 
                                        
     
                 
             
                                         
  
                      
              
        
            
                                 
               
                          
                 
         
   
                                                 
                              
         
                                   
          
         
            
                                         
    
                        
                          
       
     
               
                
             
                
      
      
                
               
               
   
      
                      
                      
           
            
    
       
   
    
  
                      
                                                              
  
  
    
          
                         
                         
  
        
       
  
        
       
                           
                                 
         
 
                      
      
              
          
       
      
               
  
                       
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
    
          
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                                  
 
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                               
 
        
   
  
   
             
  
 
             
          
      
  
          
  
   
   
   
   
   
        
 
  
                         
     
      
      
      
     
         
     
    
     
     
    
    
    
    
     
     
     
     
       
    
   
 
    
     
     
     
      
  
    
   
 
     
  
       
    
  
     
     
  
  
  
     
     
     
     
     
     
     
     
     
    
         
     
   
   
   
   
   
   
   
   
   
    
    
    
    
    
    
    
   
             
   
  
 
  
 
 
  
  
  
 
 
 
  
  
  
  
 
   
      
    
   
  
  
  
 
 
  
  
  
 
 
 
  
  
  
  
 
      
    
   
  
 
  
 
 
  
  
  
 
 
 
  
  
  
  
 
    
      
   
   
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
 
                 
  
   
  
 
 
   
 
  
  
  
 
  
  
 
  
  
 
  
  
       
 
   
  
 
 
   
 
  
  
  
 
  
  
 
  
  
 
  
           
   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
         
  
   
   
   
   
  
  
  
  
  
  
  
  
 
   
   
   
  
        
 
  
   
   
   
   
   
   
   
   
   
   
  
   
   
   
   
  
            
   
  
 
  
 
 
  
  
  
 
 
 
  
  
  
  
 
  
 
   
  
 
  
 
 
  
  
  
 
 
 
  
  
  
  
 
          
 
   
  
 
  
 
 
  
  
  
 
 
 
  
  
  
  
 
   
         
  
 
  
   
  
 
 
  
  
  
  
  
  
  
  
 
   
   
   
  
     
         
   
   
  
  
  
  
  
  
  
  
  
  
  
   
   
   
   
  
            
   
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
 
       
 
   
  
 
 
  
  
  
  
  
  
  
  
 
   
   
   
  
   
  
   
  
 
 
  
  
  
  
  
  
  
  
 
   
   
   
  
     
       
   
  
  
   
  
  
  
  
  
  
  
  
 
   
   
   
  
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                                 
      
 
        
         
             
  
 
             
          
      
  
          
  
   
   
   
   
   
   
     
     
     
     
     
     
     
           
      
           
         
     
    
     
     
    
    
    
    
     
     
     
     
       
    
   
 
    
     
     
     
      
  
    
   
 
     
  
       
    
  
     
     
  
  
  
     
     
     
     
     
     
     
     
     
    
         
     
   
   
   
   
   
   
   
   
   
    
    
    
    
    
    
    
   
         
   
  
  
   
  
  
  
  
  
  
  
   
  
   
   
   
  
     
  
  
  
  
  
  
  
  
  
  
  
   
  
  
  
  
  
           
   
  
  
  
  
  
  
  
  
  
  
   
  
  
  
  
 
            
        
  
  
  
   
   
   
   
   
   
   
 
  
  
  
  
 
          
  
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
  
     
             
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
  
             
  
  
  
  
  
  
  
  
  
  
  
  
   
   
   
   
   
  
             
    
  
  
  
  
  
  
  
  
  
  
  
   
  
  
  
  
  
                
  
  
  
  
  
   
   
   
  
  
   
   
   
  
  
   
  
  
            
  
                              
           
                     
     
                     
                     
                                      
          
  
       
                      
   
    
                                         
         
                                   
   
     
                                            
                         
   
                   
          
    
  
    
 
                      
                       
    
    
     
           
  
                    
         
           
                         
                     
        
               
 
   
  
                                  
  
      
                                   
        
                        
        
 
                                         
                          
 
   
                 
   
                      
       
                 
   
                      
         
            
   
                                  
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                                 
      
         
      
   
                                                                                           
            
  
                                                 
                                  
   
                                      
                                    
       
       
   
             
                                  
         
        
  
                        
  
                             
                                     
                                        
   
                   
   
    
                     
 
                                           
                      
              
                     
 
   
                           
    
                            
         
           
                                               
           
                      
     
          
              
    
                         
         
      
    
    
                 
           
                               
                                   
 
   
                              
 
  
  
  
   
      
   
         
   
          
   
              
   
          
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
           
                           
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
           
                    
                      
              
     
    
               
 
                                      
                    
  
           
        
         
  
      
  
  
    
  
  
    
  
         
  
         
  
      
  
      
  
    
    
  
        
  
      
  
    
  
       
  
                
  
       
  
    
     
  
            
     
  
  
              
     
  
    
  
    
  
               
  
            
  
    
 
            
  
    
  
       
  
       
 
          
  
  
   
    
    
      
  
   
           
  
          
  
    
          
        
  
           
           
        
 
     
    
  
        
  
      
  
   
 
      
  
          
       
 
           
  
  
               
     
 
            
  
            
     
 
 
                 
 
  
   
 
  
  
 
  
    
         
  
          
  
  
         
  
     
  
  
             
  
   
  
  
          
  
  
    
     
            
  
  
   
  
  
 
    
  
  
    
  
  
          
  
        
 
          
  
     
    
  
             
     
  
              
 
       
     
  
       
       
  
     
  
 
  
     
    
 
  
     
  
 
  
     
   
 
  
       
    
     
  
    
    
      
  
       
 
 
 
  
       
 
 
         
  
      
 
    
  
  
    
  
          
  
   
        
  
   
  
            
  
     
  
     
  
      
  
  
       
  
      
  
     
  
         
     
  
    
  
       
        
  
     
     
 
  
    
 
  
     
 
  
   
  
  
    
 
  
 
 
 
  
  
    
  
  
          
 
 
                   
             
                   
                       
       
         
      
   
 
   
             
       
             
                                          
 
                       
       
  
   
  
  
      
                       
     
     
    
               
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                               
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                 
             
 
      
             
      
                
  
   
    
    
     
     
     
     
     
     
     
     
      
     
       
        
   
             
       
       
       
       
       
       
       
       
       
       
       
      
                       
  
   
   
   
   
   
   
   
   
   
   
   
  
                                            
               
        
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                                                  
                          
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
                                    
    
                      
   
                                 
      
            
       
      
   
      
            
                                   
     
   
      
         
                  
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
             
                      
          
         
  
           
   
             
      


         
    
           
           
      
 
             
 
 
 
 
 
             
                      
          
         
  
           
   
             
      






Official Title: 
A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, 
Tolerability and Efficacy of IONIS-AGT-LRX, an Antisense Inhibitor 
Administered Subcutaneously for 6 Weeks to Hypertensive Subjects with 
Controlled Blood Pressure 
NCT Number: 
NCT03714776 
Document Date: 
SAP Version 1.1 : 14 November 2019