Nirmatrelvir plus ritonavir, molnupiravir and remdesivir are antiviral medicines. When being assessed for treatment, a doctor will advise which treatment is most suitable for you.

Some treatments come as capsules or tablets that you swallow. Others are given to you through a drip in your arm infusion , usually in a hospital or local health centre.

These treatments can help some people manage their COVID symptoms and reduce the risk of becoming seriously ill. If you need to go into hospital for COVID, you may get other treatments.

Local NHS organisations are responsible for arranging COVID treatments. The way you get treatment will depend on where you live. Your local integrated care board ICB can give you more information. If you think you're in the highest risk group and need to access COVID treatment, follow these steps to be considered for a referral.

If you're eligible for COVID treatment, you should keep rapid lateral flow tests at home. You may be able to pick up free rapid lateral flow test kits from your local pharmacy if you're eligible for COVID treatment. Your local integrated care board ICB may be able to give you more information on where you can collect free tests.

Find your local integrated care board ICB. Someone else can collect free tests on your behalf, for example, a friend, relative or carer. If you do not have a friend, relative or carer who can collect your tests for you, you may be able to book a volunteer responder by calling If you test positive within five days of experiencing COVID symptoms or have symptoms and are in close contact with someone recently diagnosed with COVID, you can consult a healthcare provider either on-site or through telehealth.

If eligible, you can receive a prescription for an oral antiviral treatment and have it filled at the same location. This service is available for uninsured patients at no out-of-pocket cost at participating locations. Oral antiviral treatment helps your body fight COVID by stopping the SARS-CoV-2 virus which causes COVID from multiplying.

By getting treatment, you could have less severe symptoms and lower the chances of your illness worsening and needing hospital care. Antiviral therapies for COVID are available for individuals with mild to moderate symptoms, who are not in the hospital, who have had symptoms for five days or less, and who are at high risk for severe illness.

For more information, see What Are Oral Antivirals information sheet PDF Available in additional languages. Uninsured individuals can seek services at several clinics, including Federally Qualified Health Centers FQHCs such as:.

Uninsured individuals seeking COVID therapeutics or other health care coverage can also access Medicaid enrollment and healthcare marketplace enrollment. For more information about COVID therapeutics, visit the Centers for Disease Control and Prevention's COVID Therapeutics page.

Pregnancy Influenza HIV. Home Management Clinical Management of Adults Nonhospitalized Adults: Therapeutic Management. Management Clinical Management of Adults Clinical Management of Adults Summary.

Clinical Management of Children Summary. Summary Recommendations. Introduction to Critical Care for Children. Guideline PDFs Section Only PDF KB Full Guideline PDF 5. Related Content Guidelines Archive How to Cite These Guidelines.

Therapeutic Management of Nonhospitalized Adults With COVID Last Updated: November 2, Symptom management should be initiated for all nonhospitalized adults with mild to moderate COVID Table 2a.

Therapeutic Management of Nonhospitalized Adults With Mild to Moderate COVID Who Do Not Require Supplemental Oxygen. All Patients.

Symptom management should be initiated for all patients AIII. The Panel recommends against the use of dexamethasone a or other systemic corticosteroids in the absence of another indication AIIb. There is currently a lack of safety and efficacy data on the use of dexamethasone in outpatients with COVID Using systemic glucocorticoids in outpatients with COVID may cause harm.

Patients Who Are at High Risk of Progressing to Severe COVID b,c. Preferred therapies. Listed in order of preference: Ritonavir-boosted nirmatrelvir Paxlovid d AIIa ; see footnote on drug interactions e Remdesivir d,f BIIa Alternative therapy.

For use when the preferred therapies are not available, feasible to use, or clinically appropriate: Molnupiravir d,g,h CIIa. For a list of risk factors, see the CDC webpage Underlying Medical Conditions Associated With Higher Risk for Severe COVID When deciding whether to prescribe antiviral treatment to a patient who has been vaccinated, clinicians should be aware of the conditions associated with a high risk of disease progression.

These conditions include older age, a prolonged amount of time since the most recent vaccine dose e. The number and severity of risk factors also affects the level of risk. For a discussion of potential treatment options for patients who are immunocompromised and have prolonged COVID symptoms and evidence of ongoing viral replication, see below and Special Considerations in People Who Are Immunocompromised.

Ritonavir-boosted nirmatrelvir has significant drug-drug interactions. See Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir Paxlovid and Concomitant Medications for more information.

Administration of remdesivir requires an IV infusion once daily for 3 days. Molnupiravir appears to have lower efficacy than the other options recommended by the Panel. Therefore, it should be considered when the other options are not available, feasible to use, or clinically appropriate.

Symptom Management Treatment of symptoms includes using over-the-counter antipyretics, analgesics, or antitussives for fever, headache, myalgias, and cough.

Strategies for the Use of Ritonavir-Boosted Nirmatrelvir Because ritonavir is a strong cytochrome P 3A4 inhibitor and a P-glycoprotein inhibitor, it may increase blood concentrations of certain concomitant medications and increase the potential for serious drug toxicities.

Strategies for the Use of Remdesivir Advanced planning e. b Vaccinated individuals who are not up to date with their immunizations are likely at higher risk for severe disease; patients within this tier who are in this situation should be prioritized for treatment.

See the CDC webpage Stay Up to Date with COVID Vaccines for more information. Patients Who Are Immunocompromised and Have Prolonged Symptoms and Evidence of Ongoing Viral Replication For patients who are immunocompromised and have prolonged COVID symptoms and evidence of ongoing viral replication e.

Additional Information on Ritonavir-Boosted Nirmatrelvir Nirmatrelvir is an orally bioavailable protease inhibitor that is active against M PRO , a viral protease that plays an essential role in viral replication. Additional Information on Remdesivir Remdesivir is a nucleotide prodrug of an adenosine analog that inhibits SARS-CoV-2 replication.

Additional Information on Molnupiravir Molnupiravir is the oral prodrug of beta-D-N4-hydroxycytidine, a ribonucleoside that has shown antiviral activity against SARS-CoV-2 in vitro and in clinical trials. Viral Rebound and Symptom Recurrence Observational studies and the EPIC-HR and MOVe-OUT trials have described SARS-CoV-2 viral rebound and the recurrence of COVID symptoms in some patients who have completed treatment with ritonavir-boosted nirmatrelvir or molnupiravir.

Immunomodulators The Panel recommends against the use of dexamethasone or other systemic corticosteroids to treat outpatients with mild to moderate COVID who do not require hospitalization or supplemental oxygen AIIb. References Centers for Disease Control and Prevention.

Underlying medical conditions associated with higher risk for severe COVID information for healthcare professionals. Accessed October 17, Mackey K, Ayers CK, Kondo KK, et al.

Racial and ethnic disparities in COVIDrelated infections, hospitalizations, and deaths: a systematic review.

Ann Intern Med. Wu EL, Kumar RN, Moore WJ, et al. Disparities in COVID monoclonal antibody delivery: a retrospective cohort study. J Gen Intern Med. Gold JAW, Kelleher J, Magid J, et al. Dispensing of oral antiviral drugs for treatment of COVID by ZIP code-level social vulnerability—United States, December 23, —May 21, MMWR Morb Mortal Wkly Rep.

Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID N Engl J Med. Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent progression to severe COVID in outpatients. Ritonavir-boosed nirmatrelvir Paxlovid [package insert].

Food and Drug Administration. Hiremath S, Blake PG, Yeung A, et al. Clin J Am Soc Nephrol. Toussi SS, Neutel JM, Navarro J, et al. Clin Pharmacol Ther. University of Liverpool. Prescribing resources. Accessed July 13, Ontario Health. Food and Drug Administration Center for Drug Evaluation and Research.

Antimicrobial drugs advisory committee meeting. Huygens S, Gharbharan A, Serroukh Y, et al. J Antimicrob Chemother. J Microbiol Immunol Infect. Mikulska M, Sepulcri C, Dentone C, et al.

Triple combination therapy with two antivirals and monoclonal antibodies for persistent or relapsed SARS-CoV-2 infection in immunocompromised patients. Clin Infect Dis. Graziani L, Gori L, Manciulli T, et al.

Antiviral drugs are a class of medication used for treating viral infections. They should be distinguished from virucides , which are not medication but deactivate or destroy virus particles, either inside or outside the body.

Natural virucides are produced by some plants such as eucalyptus and Australian tea trees. Most of the antiviral drugs now available are designed to help deal with HIV , herpes viruses , the hepatitis B and C viruses, and influenza A and B viruses.

Viruses use the host's cells to replicate and this makes it difficult to find targets for the drug that would interfere with the virus without also harming the host organism's cells. Moreover, the major difficulty in developing vaccines and antiviral drugs is due to viral variation. The emergence of antivirals is the product of a greatly expanded knowledge of the genetic and molecular function of organisms, allowing biomedical researchers to understand the structure and function of viruses, major advances in the techniques for finding new drugs, and the pressure placed on the medical profession to deal with the human immunodeficiency virus HIV , the cause of acquired immunodeficiency syndrome AIDS.

The first experimental antivirals were developed in the s, mostly to deal with herpes viruses , and were found using traditional trial-and-error drug discovery methods. They then introduced into the cultures chemicals which they thought might inhibit viral activity and observed whether the level of virus in the cultures rose or fell.

Chemicals that seemed to have an effect were selected for closer study. This was a very time-consuming, hit-or-miss procedure, and in the absence of a good knowledge of how the target virus worked, it was not efficient in discovering effective antivirals which had few side effects.

Only in the s, when the full genetic sequences of viruses began to be unraveled, did researchers begin to learn how viruses worked in detail, and exactly what chemicals were needed to thwart their reproductive cycle. The general idea behind modern antiviral drug design is to identify viral proteins, or parts of proteins, that can be disabled.

For example, a researcher might target a critical enzyme synthesized by the virus, but not by the patient, that is common across strains, and see what can be done to interfere with its operation.

Once targets are identified, candidate drugs can be selected, either from drugs already known to have appropriate effects or by actually designing the candidate at the molecular level with a computer-aided design program. The target proteins can be manufactured in the lab for testing with candidate treatments by inserting the gene that synthesizes the target protein into bacteria or other kinds of cells.

The cells are then cultured for mass production of the protein, which can then be exposed to various treatment candidates and evaluated with "rapid screening" technologies.

Viruses consist of a genome and sometimes a few enzymes stored in a capsule made of protein called a capsid , and sometimes covered with a lipid layer sometimes called an 'envelope'. Viruses cannot reproduce on their own and instead propagate by subjugating a host cell to produce copies of themselves, thus producing the next generation.

Researchers working on such " rational drug design " strategies for developing antivirals have tried to attack viruses at every stage of their life cycles. Some species of mushrooms have been found to contain multiple antiviral chemicals with similar synergistic effects.

Viral life cycles vary in their precise details depending on the type of virus, but they all share a general pattern:. One antiviral strategy is to interfere with the ability of a virus to infiltrate a target cell. The virus must go through a sequence of steps to do this, beginning with binding to a specific " receptor " molecule on the surface of the host cell and ending with the virus "uncoating" inside the cell and releasing its contents.

Viruses that have a lipid envelope must also fuse their envelope with the target cell, or with a vesicle that transports them into the cell before they can uncoat. This strategy of designing drugs can be very expensive, and since the process of generating anti-idiotypic antibodies is partly trial and error, it can be a relatively slow process until an adequate molecule is produced.

A very early stage of viral infection is viral entry , when the virus attaches to and enters the host cell. A number of "entry-inhibiting" or "entry-blocking" drugs are being developed to fight HIV. HIV most heavily targets a specific type of lymphocyte known as "helper T cells", and identifies these target cells through T-cell surface receptors designated " CD4 " and " CCR5 ".

Attempts to interfere with the binding of HIV with the CD4 receptor have failed to stop HIV from infecting helper T cells, but research continues on trying to interfere with the binding of HIV to the CCR5 receptor in hopes that it will be more effective.

HIV infects a cell through fusion with the cell membrane, which requires two different cellular molecular participants, CD4 and a chemokine receptor differing depending on the cell type. At least one of these entry inhibitors—a biomimetic peptide called Enfuvirtide , or the brand name Fuzeon—has received FDA approval and has been in use for some time.

Potentially, one of the benefits from the use of an effective entry-blocking or entry-inhibiting agent is that it potentially may not only prevent the spread of the virus within an infected individual but also the spread from an infected to an uninfected individual.

One possible advantage of the therapeutic approach of blocking viral entry as opposed to the currently dominant approach of viral enzyme inhibition is that it may prove more difficult for the virus to develop resistance to this therapy than for the virus to mutate or evolve its enzymatic protocols.

Inhibitors of uncoating have also been investigated. Amantadine and rimantadine have been introduced to combat influenza. These agents act on penetration and uncoating. Pleconaril works against rhinoviruses , which cause the common cold , by blocking a pocket on the surface of the virus that controls the uncoating process.

This pocket is similar in most strains of rhinoviruses and enteroviruses , which can cause diarrhea, meningitis , conjunctivitis , and encephalitis.

Some scientists are making the case that a vaccine against rhinoviruses, the predominant cause of the common cold, is achievable.

Vaccines that combine dozens of varieties of rhinovirus at once are effective in stimulating antiviral antibodies in mice and monkeys, researchers reported in Nature Communications in Rhinoviruses are the most common cause of the common cold; other viruses such as respiratory syncytial virus , parainfluenza virus and adenoviruses can cause them too.

Although rhinoviruses come in many varieties, they do not drift to the same degree that influenza viruses do. A mixture of 50 inactivated rhinovirus types should be able to stimulate neutralizing antibodies against all of them to some degree. A second approach is to target the processes that synthesize virus components after a virus invades a cell.

One way of doing this is to develop nucleotide or nucleoside analogues that look like the building blocks of RNA or DNA , but deactivate the enzymes that synthesize the RNA or DNA once the analogue is incorporated.

This approach is more commonly associated with the inhibition of reverse transcriptase RNA to DNA than with "normal" transcriptase DNA to RNA. The first successful antiviral, aciclovir , is a nucleoside analogue, and is effective against herpesvirus infections.

The first antiviral drug to be approved for treating HIV, zidovudine AZT , is also a nucleoside analogue. An improved knowledge of the action of reverse transcriptase has led to better nucleoside analogues to treat HIV infections.

One of these drugs, lamivudine , has been approved to treat hepatitis B, which uses reverse transcriptase as part of its replication process. Researchers have gone further and developed inhibitors that do not look like nucleosides, but can still block reverse transcriptase.

Another target being considered for HIV antivirals include RNase H —which is a component of reverse transcriptase that splits the synthesized DNA from the original viral RNA. Another target is integrase , which integrate the synthesized DNA into the host cell genome.

Examples of integrase inhibitors include raltegravir , elvitegravir , and dolutegravir. Once a virus genome becomes operational in a host cell, it then generates messenger RNA mRNA molecules that direct the synthesis of viral proteins. Production of mRNA is initiated by proteins known as transcription factors.

Several antivirals are now being designed to block attachment of transcription factors to viral DNA. Genomics has not only helped find targets for many antivirals, it has provided the basis for an entirely new type of drug, based on "antisense" molecules.

These are segments of DNA or RNA that are designed as complementary molecule to critical sections of viral genomes, and the binding of these antisense segments to these target sections blocks the operation of those genomes. A phosphorothioate antisense drug named fomivirsen has been introduced, used to treat opportunistic eye infections in AIDS patients caused by cytomegalovirus , and other antisense antivirals are in development.

An antisense structural type that has proven especially valuable in research is morpholino antisense. Yet another antiviral technique inspired by genomics is a set of drugs based on ribozymes , which are enzymes that will cut apart viral RNA or DNA at selected sites.

In their natural course, ribozymes are used as part of the viral manufacturing sequence, but these synthetic ribozymes are designed to cut RNA and DNA at sites that will disable them.

A ribozyme antiviral to deal with hepatitis C has been suggested, [28] and ribozyme antivirals are being developed to deal with HIV. This is part of a broader effort to create genetically modified cells that can be injected into a host to attack pathogens by generating specialized proteins that block viral replication at various phases of the viral life cycle.

Interference with post translational modifications or with targeting of viral proteins in the cell is also possible. Some viruses include an enzyme known as a protease that cuts viral protein chains apart so they can be assembled into their final configuration.

HIV includes a protease, and so considerable research has been performed to find " protease inhibitors " to attack HIV at that phase of its life cycle.

Protease inhibitors have also been seen in nature. A protease inhibitor was isolated from the shiitake mushroom Lentinus edodes. Most viruses produce long dsRNA helices during transcription and replication. In contrast, uninfected mammalian cells generally produce dsRNA helices of fewer than 24 base pairs during transcription.

DRACO double-stranded RNA activated caspase oligomerizer is a group of experimental antiviral drugs initially developed at the Massachusetts Institute of Technology. In cell culture, DRACO was reported to have broad-spectrum efficacy against many infectious viruses, including dengue flavivirus , Amapari and Tacaribe arenavirus , Guama bunyavirus , H1N1 influenza and rhinovirus , and was additionally found effective against influenza in vivo in weanling mice.

It was reported to induce rapid apoptosis selectively in virus-infected mammalian cells, while leaving uninfected cells unharmed. The procaspases transactivate via cleavage, activate additional caspases in the cascade, and cleave a variety of cellular proteins, thereby killing the cell.

Rifampicin acts at the assembly phase. The final stage in the life cycle of a virus is the release of completed viruses from the host cell, and this step has also been targeted by antiviral drug developers.

Two drugs named zanamivir Relenza and oseltamivir Tamiflu that have been recently introduced to treat influenza prevent the release of viral particles by blocking a molecule named neuraminidase that is found on the surface of flu viruses, and also seems to be constant across a wide range of flu strains.

Rather than attacking viruses directly, a second category of tactics for fighting viruses involves encouraging the body's immune system to attack them. Some antivirals of this sort do not focus on a specific pathogen, instead stimulating the immune system to attack a range of pathogens.

One of the best-known of this class of drugs are interferons , which inhibit viral synthesis in infected cells. A more specific approach is to synthesize antibodies , protein molecules that can bind to a pathogen and mark it for attack by other elements of the immune system.

Once researchers identify a particular target on the pathogen, they can synthesize quantities of identical "monoclonal" antibodies to link up that target. A monoclonal drug is now being sold to help fight respiratory syncytial virus in babies, [39] and antibodies purified from infected individuals are also used as a treatment for hepatitis B.

Antiviral resistance can be defined by a decreased susceptibility to a drug caused by changes in viral genotypes. In cases of antiviral resistance, drugs have either diminished or no effectiveness against their target virus.

The Centers for Disease Control and Prevention CDC inclusively recommends anyone six months and older to get a yearly vaccination to protect them from influenza A viruses H1N1 and H3N2 and up to two influenza B viruses depending on the vaccination.

However, vaccines are preventative and are not generally used once a patient has been infected with a virus. Additionally, the availability of these vaccines can be limited based on financial or locational reasons which can prevent the effectiveness of herd immunity, making effective antivirals a necessity.

The three FDA-approved neuraminidase antiviral flu drugs available in the United States, recommended by the CDC, include: oseltamivir Tamiflu , zanamivir Relenza , and peramivir Rapivab. Currently, neuraminidase inhibitors NAIs are the most frequently prescribed antivirals because they are effective against both influenza A and B.

However, antiviral resistance is known to develop if mutations to the neuraminidase proteins prevent NAI binding. Furthermore, a study published in in Nature Biotechnology emphasized the urgent need for augmentation of oseltamivir stockpiles with additional antiviral drugs including zanamivir.

This finding was based on a performance evaluation of these drugs supposing the H1N1 'Swine Flu' neuraminidase NA were to acquire the oseltamivir-resistance HisTyr mutation, which is currently widespread in seasonal H1N1 strains.

Rebound has been observed not only with Paxlovid but also in patients receiving no treatment and in patients receiving other COVID therapeutics.

Recent studies suggest patients with rebound have mild symptoms and have an extremely low probability of developing severe COVID If you were treated with Paxlovid and recovered, but symptoms came back and you had a positive test result, follow guidance on Sick or Test Positive for how long to stay home and when to wear a mask.

Let your health care provider know your symptoms have returned and let them know if you have any questions. At this time, you should not need to receive other COVID medications.

Molnupiravir is an oral antiviral medication that works by blocking the virus from making copies of itself replicating. It has been authorized for use in adults ages 18 and older with mild to moderate COVID, and at high risk for severe disease.

Molnupiravir is to be started within five days of symptoms starting, so it's important for people at high risk to connect with their health care provider right away. This medication is not recommended for use while pregnant or breastfeeding. Talk to your health care provider about other treatment options if you are pregnant or breastfeeding, and people of childbearing age should talk to their provider about preventing pregnancy if using this treatment.

COVID Medications: Oral Antivirals PDF Handout summary of when oral antivirals are used to treat COVID Other languages: COVID Medications: Oral Antivirals.

Remdesivir NIH is an antiviral drug that works by blocking the virus from making copies of itself replicating. Remdesivir is given through a needle in the vein intravenously over time, which is called an IV infusion.

Remdesivir is approved for outpatient treatment of adults and children who are at high risk for severe COVID It should be started as soon as possible, with outpatient treatment beginning within seven days of symptoms developing.

The treatment is given as a series of three IV infusions, given once a day for three consecutive days.

Not all health care facilities can offer outpatient remdesivir treatment — patients should speak to their health care provider to see if it may be a potential treatment option. Remdesivir is also used to treat patients who are hospitalized with more severe illness due to COVID If you are hospitalized due to COVID, your health care providers will decide if remdesivir or other treatments are needed.

Antibodies are proteins that people's bodies make to fight viruses, such as the virus that causes COVID Antibodies made in a laboratory act a lot like natural antibodies to limit the amount of virus in your body.

They are called monoclonal antibodies. Antibodies are usually given into a vein by intravenous IV infusion or into the skin by subcutaneous SQ injection. There are currently no monoclonal antibodies authorized for use for the treatment or prevention of COVID in the U.

due to lack of effectiveness against currently circulating variants of SARS-CoV Your health care provider can help determine if another type of COVID medication is right for you. As of Jan. FDA announces Evusheld is not currently authorized for emergency use in the U.

For more information about what you can do to protect yourself if you have a weakened immune system, go to CDC: Information for Persons Who Are Immunocompromised Regarding Prevention and Treatment of SARS-CoV-2 Infection in the Context of Currently Circulating Omicron Lineages - United States, January Pregnant people and their babies are at high risk for serious illness from COVID People who are pregnant should talk with their doctor or other health care provider.

Oral antivirals There are limited specific safety data on the use of antiviral treatment for COVID in people who are pregnant or breastfeeding, although to date no safety concerns have been identified when these patients have taken antivirals. Studies suggest there is no increased risk of severe COVID illness in people who experience COVID rebound after antiviral treatment.

The benefits of COVID treatment outweigh the risk of rebound if you are at high risk for severe COVID Talk to your healthcare provider if you think you may have rebound. Watch ASL Video: Get Treatment for COVID Click the button below or call TTY to find a location that offers testing and treatment or a pharmacy where you can fill your prescription.

COVID oral antiviral treatments, Paxlovid and Lagevrio, began transitioning to the commercial market on November 1, If you get sick, Paxlovid and Lagevrio will continue to be available during and after this transition.

Patient assistance programs are available to people who are underinsured, uninsured, or on Medicaid or Medicare to lower their out-of-pocket costs. Call ahead to your healthcare provider and insurer to confirm supply and coverage eligibility.

The right medications for COVID can help. But people have been seriously harmed and even died after taking products not approved for use to treat or prevent COVID, even products approved or prescribed for other uses. Talk to a healthcare provider about taking medications to treat COVID Home Test to Treat : The Home Test to Treat program provides access to free dispensing fees may apply COVID and flu testing, telehealth visits, and treatment for anyone who tests positive for either condition.

Treatment can be shipped to you or picked up at a local pharmacy at no cost for those eligible. Regardless of insurance status, anyone with a current positive COVID or flu test may enroll for free telehealth and treatment.

Call TTY to learn more about the Home Test to Treat program. COVID vaccines available in the United States effectively protect people from getting seriously ill, being hospitalized, and even dying. As with vaccines for other diseases, you are protected best when you stay up to date.

CDC recommends that everyone who is eligible stay up to date on their COVID vaccines. To find COVID vaccine locations near you: Search vaccines. gov , text your ZIP code to , or call Skip directly to site content Skip directly to search.

Español Other Languages. Important update: Healthcare facilities. CDC has updated select ways to operate healthcare systems effectively in response to COVID vaccination. Learn more. Find the latest information: Recommendations for Fully Vaccinated People COVID Homepage. COVID Treatments and Medications COVID Treatments and Medications.