Accessibility Statement Skip Navigation
  • Resources
  • Blog
  • Journalists
  • Webcasts
  • Data Privacy
  • Français
  • my CNW 
    • Login
    • Register
  • Client Login 
    • Online Member Centre
    • Next Gen Communications Cloud
    • Cision Communications Cloud®
  • Sign Up
  • Send a Release
Return to PR Newswire homepage
  • News
  • Products
  • Contact
When typing in this field, a list of search results will appear and be automatically updated as you type.

Searching for your content...

No results found. Please change your search terms and try again.
Advanced Search
  • News in Focus
      • Browse News Releases

      • All News Releases
      • All Public Company
      • News Releases Overview

      • Multimedia Gallery

      • All Multimedia
      • All Photos
      • All Videos
      • Multimedia Gallery Overview

      • Trending Topics

      • All Trending Topics
  • Business
      • Auto & Transportation

      • All Automotive & Transportation
      • Aerospace, Defense
      • Air Freight
      • Airlines & Aviation
      • Automotive
      • Maritime & Shipbuilding
      • Railroads and Intermodal Transportation
      • Supply Chain/Logistics
      • Transportation, Trucking & Railroad
      • Travel
      • Trucking and Road Transportation
      • Auto & Transportation Overview

      • View All Auto & Transportation

      • Business Technology

      • All Business Technology
      • Blockchain
      • Broadcast Tech
      • Computer & Electronics
      • Computer Hardware
      • Computer Software
      • Data Analytics
      • Electronic Commerce
      • Electronic Components
      • Electronic Design Automation
      • Financial Technology
      • High Tech Security
      • Internet Technology
      • Nanotechnology
      • Networks
      • Peripherals
      • Semiconductors
      • Business Technology Overview

      • View All Business Technology

      • Entertain­ment & Media

      • All Entertain­ment & Media
      • Advertising
      • Art
      • Books
      • Entertainment
      • Film and Motion Picture
      • Magazines
      • Music
      • Publishing & Information Services
      • Radio & Podcast
      • Television
      • Entertain­ment & Media Overview

      • View All Entertain­ment & Media

      • Financial Services & Investing

      • All Financial Services & Investing
      • Accounting News & Issues
      • Acquisitions, Mergers and Takeovers
      • Banking & Financial Services
      • Bankruptcy
      • Bond & Stock Ratings
      • Conference Call Announcements
      • Contracts
      • Cryptocurrency
      • Dividends
      • Earnings
      • Earnings Forecasts & Projections
      • Financing Agreements
      • Insurance
      • Investments Opinions
      • Joint Ventures
      • Mutual Funds
      • Private Placement
      • Real Estate
      • Restructuring & Recapitalization
      • Sales Reports
      • Shareholder Activism
      • Shareholder Meetings
      • Stock Offering
      • Stock Split
      • Venture Capital
      • Financial Services & Investing Overview

      • View All Financial Services & Investing

      • General Business

      • All General Business
      • Awards
      • Commercial Real Estate
      • Corporate Expansion
      • Earnings
      • Environmental, Social and Governance (ESG)
      • Human Resource & Workforce Management
      • Licensing
      • New Products & Services
      • Obituaries
      • Outsourcing Businesses
      • Personnel Announcements
      • Real Estate Transactions
      • Residential Real Estate
      • Small Business Services
      • Socially Responsible Investing
      • Surveys, Polls and Research
      • Trade Show News
      • General Business Overview

      • View All General Business

  • Science & Tech
      • Consumer Technology

      • All Consumer Technology
      • Artificial Intelligence
      • Blockchain
      • Cloud Computing/Internet of Things
      • Computer Electronics
      • Computer Hardware
      • Computer Software
      • Consumer Electronics
      • Cryptocurrency
      • Data Analytics
      • Electronic Commerce
      • Electronic Gaming
      • Financial Technology
      • Mobile Entertainment
      • Multimedia & Internet
      • Peripherals
      • Social Media
      • STEM (Science, Tech, Engineering, Math)
      • Supply Chain/Logistics
      • Wireless Communications
      • Consumer Technology Overview

      • View All Consumer Technology

      • Energy & Natural Resources

      • All Energy
      • Alternative Energies
      • Chemical
      • Electrical Utilities
      • Gas
      • General Manufacturing
      • Mining
      • Mining & Metals
      • Oil & Energy
      • Oil and Gas Discoveries
      • Utilities
      • Water Utilities
      • Energy & Natural Resources Overview

      • View All Energy & Natural Resources

      • Environ­ment

      • All Environ­ment
      • Conservation & Recycling
      • Environmental Issues
      • Environmental Policy
      • Environmental Products & Services
      • Green Technology
      • Natural Disasters
      • Environ­ment Overview

      • View All Environ­ment

      • Heavy Industry & Manufacturing

      • All Heavy Industry & Manufacturing
      • Aerospace & Defense
      • Agriculture
      • Chemical
      • Construction & Building
      • General Manufacturing
      • HVAC (Heating, Ventilation and Air-Conditioning)
      • Machinery
      • Machine Tools, Metalworking and Metallurgy
      • Mining
      • Mining & Metals
      • Paper, Forest Products & Containers
      • Precious Metals
      • Textiles
      • Tobacco
      • Heavy Industry & Manufacturing Overview

      • View All Heavy Industry & Manufacturing

      • Telecomm­unications

      • All Telecomm­unications
      • Carriers and Services
      • Mobile Entertainment
      • Networks
      • Peripherals
      • Telecommunications Equipment
      • Telecommunications Industry
      • VoIP (Voice over Internet Protocol)
      • Wireless Communications
      • Telecomm­unications Overview

      • View All Telecomm­unications

  • Lifestyle & Health
      • Consumer Products & Retail

      • All Consumer Products & Retail
      • Animals & Pets
      • Beers, Wines and Spirits
      • Beverages
      • Bridal Services
      • Cannabis
      • Cosmetics and Personal Care
      • Fashion
      • Food & Beverages
      • Furniture and Furnishings
      • Home Improvement
      • Household, Consumer & Cosmetics
      • Household Products
      • Jewelry
      • Non-Alcoholic Beverages
      • Office Products
      • Organic Food
      • Product Recalls
      • Restaurants
      • Retail
      • Supermarkets
      • Toys
      • Consumer Products & Retail Overview

      • View All Consumer Products & Retail

      • Entertain­ment & Media

      • All Entertain­ment & Media
      • Advertising
      • Art
      • Books
      • Entertainment
      • Film and Motion Picture
      • Magazines
      • Music
      • Publishing & Information Services
      • Radio & Podcast
      • Television
      • Entertain­ment & Media Overview

      • View All Entertain­ment & Media

      • Health

      • All Health
      • Biometrics
      • Biotechnology
      • Clinical Trials & Medical Discoveries
      • Dentistry
      • FDA Approval
      • Fitness/Wellness
      • Health Care & Hospitals
      • Health Insurance
      • Infection Control
      • International Medical Approval
      • Medical Equipment
      • Medical Pharmaceuticals
      • Mental Health
      • Pharmaceuticals
      • Supplementary Medicine
      • Health Overview

      • View All Health

      • Sports

      • All Sports
      • General Sports
      • Outdoors, Camping & Hiking
      • Sporting Events
      • Sports Equipment & Accessories
      • Sports Overview

      • View All Sports

      • Travel

      • All Travel
      • Amusement Parks and Tourist Attractions
      • Gambling & Casinos
      • Hotels and Resorts
      • Leisure & Tourism
      • Outdoors, Camping & Hiking
      • Passenger Aviation
      • Travel Industry
      • Travel Overview

      • View All Travel

  • Policy & Public Interest
      • Policy & Public Interest

      • All Policy & Public Interest
      • Advocacy Group Opinion
      • Animal Welfare
      • Canadian Federal Government
      • Canadian Municipal Government
      • Canadian Provincial Government
      • Corporate Social Responsibility
      • Domestic Policy
      • Economic News, Trends, Analysis
      • Education
      • Environmental
      • European Government
      • FDA Approval
      • Federal and State Legislation
      • Federal Executive Branch & Agency
      • Foreign Policy & International Affairs
      • Homeland Security
      • Labor & Union
      • Legal Issues
      • Natural Disasters
      • Not For Profit
      • Patent Law
      • Public Safety
      • Trade Policy
      • Policy & Public Interest Overview

      • View All Policy & Public Interest

  • People & Culture
      • People & Culture

      • All People & Culture
      • Aboriginal, First Nations & Native American
      • African American
      • Asian American
      • Children
      • Diversity, Equity & Inclusion
      • Hispanic
      • Lesbian, Gay & Bisexual
      • Men's Interest
      • People with Disabilities
      • Religion
      • Senior Citizens
      • Veterans
      • Women
      • People & Culture Overview

      • View All People & Culture

  • Advanced Search
  • Overview
  • Cision Communications Cloud®
  • Monitoring
  • Distribution
  • Multimedia
  • Guaranteed Paid Placement
  • AI Tools
  • IR
  • Become a Client
  • Request a Demo
  • Editorial Bureaus
  • Partnerships
  • General Enquiries
  • Media
  • Worldwide Offices
  • Hamburger menu
  • Cision Canada
  • Send a Release
  • FR
    • Phone

    • 877-269-7890 from 8 AM - 10 PM ET

    • ALL CONTACT INFO
    • Contact Cision

      877-269-7890
      from 8 AM - 10 PM ET

  • Send a Release
  • Sign Up
  • Resources
  • Blog
  • Journalists
  • Webcasts
  • GDPR
  • News in Focus
    • Browse All News
    • Multimedia Gallery
    • Trending Topics
  • Business
    • Auto & Transportation
    • Business Technology
    • Entertain­ment & Media
    • Financial Services & Investing
    • General Business
  • Science & Tech
    • Consumer Technology
    • Energy & Natural Resources
    • Environ­ment
    • Heavy Industry & Manufacturing
    • Telecomm­unications
  • Lifestyle & Health
    • Consumer Products & Retail
    • Entertain­ment & Media
    • Health
    • Sports
    • Travel
  • Policy & Public Interest
    • Policy & Public Interest
  • People & Culture
    • People & Culture
  • Send a Release
  • Sign Up
  • Resources
  • Blog
  • Journalists
  • Webcasts
  • GDPR
  • Overview
  • Cision Communications Cloud®
  • Monitoring
  • Distribution
  • Multimedia
  • Guaranteed Paid Placement
  • AI Tools
  • IR
  • Send a Release
  • Sign Up
  • Resources
  • Blog
  • Journalists
  • Webcasts
  • GDPR
  • Become a Client
  • Request a Demo
  • Editorial Bureaus
  • Partnerships
  • General Enquiries
  • Media
  • Worldwide Offices
  • Send a Release
  • Sign Up
  • Resources
  • Blog
  • Journalists
  • Webcasts
  • GDPR

ViiV Healthcare Announces Health Canada Approval for APRETUDE (Cabotegravir tablets and extended release injectable suspension) for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV Français

ViiV Healthcare (CNW Group/ViiV Healthcare)

News provided by

ViiV Healthcare

May 13, 2024, 08:01 ET

Share this article

Share toX

Share this article

Share toX

  • Approved for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV infection in at-risk adults and adolescents aged 12 years and older, weighing at least 35 kg, including men who have sex with men, transgender women, and cisgender women.
  • APRETUDE (cabotegravir extended release injectable suspension) is the first and only long-acting injectable PrEP treatment approved in Canada.
  • Given as few as six times per year after initiation and demonstrated superior efficacy to a daily oral PrEP option (FTC/TDF tablets) in reducing the risk of HIV acquisition in 2 clinical trials.1
  • The latest Canadian surveillance data shows that there were 1,833 new HIV diagnoses in 2022, a 24.9 per cent increase from 2021.2

MONTRÉAL, May 13, 2024 /CNW/ - ViiV Healthcare, the global specialist HIV company majority owned by GlaxoSmithKline plc (GSK), with Pfizer Inc. and Shionogi as shareholders, announced that Health Canada has granted approval for APRETUDE (cabotegravir tablets and extended release injectable suspension) for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in at risk individuals who are HIV-1 negative.1 APRETUDE is indicated for at-risk adults and adolescents aged 12 years and older and weighing at least 35 kg for PrEP to reduce the risk of sexually acquired HIV-1 infection.1

APRETUDE is the only long-acting injectable HIV PrEP option approved in Canada that reduces the number of doses needed for effective HIV prevention from daily pills to as few as six injections per year. Cabotegravir tablets and extended release injectable suspension for PrEP has demonstrated superior efficacy to daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF tablets) in reducing the risk of HIV acquisition in 2 clinical trials, giving Canadians more options for PrEP.1

Jean-Francois Fortin, Country Medical Director, Canada at ViiV Healthcare, said: "With the approval of APRETUDE in Canada, we are proud to be able to offer a new prevention option for Canadians at risk of acquiring HIV. We are confident that by providing another highly effective preventative option for Canadians, we are one step closer to our collective goal of ending the HIV epidemic. We look forward to working with provincial, territorial, and national health authorities to bring APRETUDE to Canadians across the country."

HIV remains a critical public health issue in Canada, with cases of HIV increasing by 24.9 per cent in 2022 from 2021.2 PrEP has been identified as an effective tool in reducing new cases of HIV, key to ending the HIV epidemic. Despite the wide availability of daily oral PrEP, inconsistent adherence as well as structural and cultural barriers lead to underutilization in key populations.

Health Canada approval was based on the results of two key phase IIb/III studies, HPTN 083 and HPTN 084, which evaluated the safety and efficacy of cabotegravir long-acting for PrEP in men who have sex with men, transgender women, and cisgender women who were at increased risk of HIV.3,4 The studies demonstrated that cabotegravir long-acting injectables for PrEP was superior to daily oral emtricitabine/tenofovir disproxil fumarate (FTC/TDF), with clinical trial participants experiencing 69 per cent lower rate of HIV acquisition compared to FTC/TDF tablets in HPTN 083, and a 90 per cent lower rate of HIV acquisition compared to FTC/TDF tablets in HPTN 084.5,6

About Cabotegravir extended release injectable suspension

Cabotegravir extended release injectable suspension is the first and only long-acting injectable pre-exposure prophylaxis (PrEP) option proven superior to daily oral FTC/TDF in reducing HIV acquisition. It is indicated for at-risk adults and adolescents aged 12 years and older, weighing at least 35 kg for PrEP to reduce the risk of sexually acquired HIV-1 infection. Cabotegravir extended release injectable suspension is administered as a single 600 mg (3-ml) intramuscular (IM) injection of cabotegravir in the buttocks by a health care professional every two months after two initiation injections administered one month apart. Cabotegravir tablets can be used as an optional oral lead-in to assess tolerability or as short-term oral PrEP in individuals who will miss planned dosing with cabotegravir extended release injectable suspension. Cabotegravir is an integrase strand transfer inhibitor (INSTI). INSTIs, like cabotegravir extended release injectable suspension, inhibit HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic disease.1

About HPTN 083 (NCT02720094 )7

The HPTN 083 trial is a phase IIb/III double blind non-inferiority trial designed to evaluate the safety and efficacy of long-acting injectable cabotegravir for HIV prevention administered every eight weeks compared to daily oral FTC/TDF tablets (200 mg/300 mg). The trial included the prespecified ability to test for superiority of long-acting cabotegravir over FTC/TDF. The trial design included an oral lead-in phase to assess tolerability to cabotegravir before administering the intramuscular injection. HPTN 083 was conducted in 4,566 men who have sex with men and transgender women who have sex with men. The study opened to enrollment in November 2016 at research centres in Argentina, Brazil, Peru, United States, South Africa, and Vietnam.5

At a pre-planned interim review of trial data, a multinational Data and Safety Monitoring Board (MDSMB) recommended that the blinded phase of HPTN 083 be stopped due to the demonstration of superior efficacy of cabotegravir when compared to daily, oral FTC/TDF and that subjects randomized to the active FTC/TDF group be offered cabotegravir. The most common adverse reactions (all grades) observed in at least 1 per cent of subjects receiving long acting cabotegravir were injection sites reactions, diarrhea, headache, pyrexia, fatigue, sleep disorders, nausea, dizziness, flatulence, and abdominal pain.5

For further information on HPTN 083 please see https://clinicaltrials.gov/ct2/show/NCT02720094.

About HPTN 084 (NCT03164564 ) 6

The HPTN 084 trial is a phase III double blind superiority trial designed to evaluate the safety and efficacy of the long-acting injectable cabotegravir for HIV prevention administered every eight weeks compared to daily oral FTC/TDF tablets (200 mg/300 mg) in 3,224 cisgender women who are at increased risk of HIV acquisition. The trial design included an oral lead-in phase to assess tolerability to cabotegravir before administering the intramuscular injection. HPTN 084 opened to enrolment in November 2017 and is being conducted at research centres in Botswana, Kenya, Malawi, South Africa, Eswatini, Uganda, and Zimbabwe.6 

The MDSMB recommended early termination of the blinded, randomized portion of HPTN 084 after an interim analysis indicated that pre-specified stopping criteria had been met (superiority of cabotegravir compared with FTC/TDF). The most common adverse reactions (all grades) observed in at least 1% of subjects receiving long acting cabotegravir were injection site reactions, diarrhea, headache, fatigue, sleep disorders, nausea, dizziness, abdominal pain, vomiting, myalgia, and rash.6 For further information please see https://clinicaltrials.gov/ct2/show/NCT03164564.

About HIV

HIV (human immunodeficiency virus) is a virus that attacks the body's immune system.8 HIV is spread by contact with certain bodily fluids of a person with HIV, most commonly during unprotected sex (sex without a condom or HIV medicine to prevent or treat HIV), or through sharing injected drug equipment.9

If HIV is not treated, it can lead to AIDS (acquired immunodeficiency virus). AIDS is the most severe stage of HIV (Stage 3).10 There is currently no cure for HIV, but with proper treatment and care, people with HIV can maintain a high quality of life and avoid passing HIV to others.

At the end of 2022, 39 million people lived with HIV around the world, with 1.3 million new diagnoses that year and 630,000 deaths from AIDS-related illnesses.11

Important Safety Information for APRETUDE for PrEP 1

The APRETUDE Product Monograph includes a Serious Warning and Precautions Box:

RISK OF DRUG RESISTANCE WITH USE OF APRETUDE IN UNDIAGNOSED HIV-1 INFECTION.1

Individuals must be tested for HIV-1 infection prior to initiating APRETUDE and should be tested for HIV-1 infection with each subsequent injection of APRETUDE. APRETUDE must not be prescribed until confirmation of negative HIV-1 infection status. Drug-resistant HIV-1 variants have been identified with use of APRETUDE by individuals with undiagnosed HIV-1 infection. Do not initiate APRETUDE if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed.1 Individuals who become infected with HIV-1 while receiving APRETUDE must transition to a complete HIV-1 treatment regimen.

The Product Monograph also includes warnings and precautions regarding hypersensitivity reactions, hepatotoxicity (liver damage) and depressive disorders.1

The Product Monograph, posted at www.viivhealthcare.ca, should be consulted for complete administration and safety information, including contraindications, additional warnings and precautions, adverse reactions and drug interactions.1 Prior to being posted online, the Product Monograph is also available by calling 1-877-393-8448. 

About ViiV Healthcare

ViiV Healthcare is a global specialist HIV company established in November 2009 by GSK (LSE: GSK) and Pfizer (NYSE: PFE) dedicated to delivering advances in treatment and care for people living with HIV and for people who are at risk of acquiring HIV. Shionogi became a ViiV shareholder in October 2012. The company's aims are to take a deeper and broader interest in HIV and AIDS than any company has done before and take a new approach to deliver effective and innovative medicines for HIV treatment and prevention, as well as support communities affected by HIV.


______________________________


1 APRETUDE Product Monograph (2024), ViiV. Available at: www.viivhealthcare.ca


2 PHAC. HIV in Canada: 2022 surveillance highlights. Available at: HIV in Canada: 2022 Surveillance highlights - Canada.ca. Accessed January 19, 2024.


3 Marzinke M, Grinsztejn B, Fogel J, Piwowar-Manning EM et al, Laboratory Analysis of HIV Infections in HPTN 083: Injectable CAB for PrEP. Conference on Retroviruses and Opportunistic Infections Abstract 153


4 Delany-Moretlwe S, Hughes JP et al. Long acting injectable cabotegravir is safe and effective in preventing HIV infection in cisgender women. HIV Research for Prevention Virtual Conference (HIVR4P 2021) abstract HY01.02, 2021.


5 Clinical Trials.gov - Safety and Efficacy Study of Injectable Cabotegravir Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), For Pre-Exposure Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women Who Have Sex with Men. Available at https://clinicaltrials.gov/ct2/show/NCT02720094. Last accessed October 2022.


6 Clinical Trials.gov - Evaluating the Safety and Efficacy of Long-Acting Injectable Cabotegravir Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women. Available at https://clinicaltrials.gov/ct2/show/NCT03164564. Last accessed October 2022.


7 DC statement on FDA approval of drug for HIV prevention. News release CDC NCHHSTP Newsroom. July 16, 2012. Accessed September 7, 2021. https://www.cdc.gov/nchhstp/newsroom/2012/fda-approvesdrugstatement.html


8 CDC. About HIV. Available at: https://www.cdc.gov/hiv/basics/whatishiv.html.


9 HIV.gov. What Are HIV and AIDS? Available at: https://www.hiv.gov/hiv-basics/overview/about-hiv-and-aids/what-are-hiv-and-aids/.


10 CDC. About HIV. Available at: https://www.cdc.gov/hiv/basics/whatishiv.html#:~:text=People%20who%20take%20HIV%20treatment,into%20Stage%203%20(AIDS)..


11 UNAIDS. Global HIV & AIDS Statistics – Fact sheet. Available at: https://www.unaids.org/en/resources/fact-sheet

SOURCE ViiV Healthcare

For more information on the company, its management, portfolio, pipeline, and commitment, please visit www.viivhealthcare.com/en-ca/ .

Modal title

Organization Profile

ViiV Healthcare

    Also from this source

  • ViiV Healthcare Announces Reimbursement for APRETUDE for HIV-1 Pre-Exposure Prophylaxis (PrEP) under the Non-Insured Health Benefits (NIHB) Program

  • Quebec becomes first province to publicly reimburse APRETUDE for HIV-1 Pre-Exposure Prophylaxis (PrEP)

  • ViiV Healthcare and the pan-Canadian Pharmaceutical Alliance (pCPA) successfully finalize negotiations for APRETUDE for HIV-1 Pre-Exposure Prophylaxis

Contact Cision

  • 866-245-2317
    from 8 AM - 10 PM ET
  • Become a Client
  • Request a Demo
  • Editorial Bureaus
  • Partnerships
  • General Enquiries
  • Media

Products

  • Cision Communications Cloud®
  • Media Monitoring
  • Content Distribution
  • Multimedia Distribution
  • Measurement & Analytics
  • Investor Relations

About

  • About Cision Canada
  • About Cision
  • Media Partners
  • Careers
  • Accessibility Statement
  • APAC
  • APAC - Simplified Chinese
  • APAC - Traditional Chinese
  • Brazil
  • Canada
  • Czech
  • Denmark
  • Finland
  • France
  • Germany
  • India
  • Indonesia
  • Israel
  • Japan
  • Korea
  • Mexico
  • Middle East
  • Middle East - Arabic
  • Netherlands
  • Norway
  • Poland
  • Portugal
  • Russia
  • Slovakia
  • Spain
  • Sweden
  • United States
  • Vietnam

My Services

  • All News Releases
  • Online Member Centre
  • Next Gen Communications Cloud
  • Cision Communications Cloud®
  • my CNW

Do not sell or share my personal information:

  • Submit via [email protected] 
  • Call Privacy toll-free: 877-297-8921

Contact Cision

Products

About

My Services
  • All News Releases
  • Online Member Centre
  • Next Gen Communications Cloud
  • Cision Communications Cloud
  • my CNW
877-269-7890
from 8 AM - 10 PM ET
  • Terms of Use
  • Information Security Policy
  • Site Map
  • Cookie Settings
  • Accessibility Statement
Copyright © 2025 CNW Group Ltd. All Rights Reserved. A Cision company.