Cushing’s syndrome is a disorder that occurs when your body makes too much of the hormone cortisol over a long period of time. Cortisol is sometimes called the “stress hormone” because it helps your body respond to stress. Cortisol also helps. maintain blood pressure. regulate blood glucose, also called blood sugar. reduce inflammation. Treatments & Medication for Cushing’s Disease in Dogs. There are two main drugs used in the treatment of Cushing’s disease in dogs. A form of the insecticide DDT (drug names include Lysodren® and mitotane) can destroy the cells that produce cortisone in the adrenal glands. Other medications such as trilostane help decrease the amount of ...The cost of diagnosis will depend on the underlying type of Cushing’s disease and any concurrent diseases that may mask certain signs. Typically, a complete diagnosis costs between $500 and $1,500. The treatment can cost from $50 to $200 a month, depending on the pup’s response to the selected medication. May 9, 2019 · Other causes include tumors that make the body produce excess cortisol. Cushing syndrome includes a range of treatable symptoms. In most cases, the syndrome is curable. NICHD is one of the many federal agencies that support and conduct research on the causes of Cushing syndrome, ways to diagnose it earlier, and better treatments. The type of Cushing's disease may determine what kind of treatment is prescribed. Veterinarians use blood tests to diagnose Cushing's and to differentiate between disease caused by the pituitary ... May 21, 2021 · Treatment of Cushing’s Disease. The location of the tumor dictates which treatment to use. More than 90 percent of dogs with CD have a pituitary-gland tumor. This type of tumor is only ... Dogs with a urine specific gravity greater than 1.025 are less likely to have Cushing’s. This is by far the most accurate, safe and effective method of diagnosing Cushing’s disease. If this test shows an elevated Cortisol-Creatinine ratio, you’ll also want to follow up with an ultrasound. I’ll talk about this next.Treatment for Cushing's Disease in dogs. As noted above, Cushing's Syndrome is due to a tumor growing in the pituitary or adrenal gland. Now it could be a benign or malignant tumor.Oct 10, 2021 · Best Cushing’s Disease Treatment For Horses. The most common and effective treatment for Cushing’s disease is a drug called pergolide mesylate. Your veterinarian may also refer to this drug as Prascend®. Pergolide comes in tablet form and is given once per day. It works by reducing the high levels of ACTH. Jun 7, 2023 · Lifestyle and home remedies. Increase activities slowly. Work up to a comfortable level of exercise or activity without overdoing it. Don't do activities that could cause you to ... Eat sensibly. Nutritious foods are a good source of fuel for your body during recovery. They also can help you lose ... Radiation treatment of pituitary tumors … or removal of the pituitary gland (hypophysectomy) has a better prognosis of 2-5 years. Adrenal tumors can sometimes be removed with surgery, giving prognosis of 18 months. Options For Conventional Cushing’s Treatment. The goal of conventional drugs for Cushing’s is two-fold:Cushing’s disease (CD) is the most common cause of endogenous Cushing’s syndrome (CS). The goal of treatment is to rapidly control cortisol excess and achieve long-term remission, to reverse the clinical features and reduce long-term complications associated with increased mortality.While pituitary surgery remains first line therapy, pituitary radiotherapy and bilateral adrenalectomy have ...Treatment for Cushing’s depends on which type your dog has and the severity of it. If your dog has adrenal-dependent Cushing’s and the tumor is benign, it could potentially be removed and ...adequate time for either drug’s effects on the adrenals to subside before switching treatments. (E.g., one month off drug; normal or increased stimulation-cortisol levels). 8) Ketoconazole. Cushing’s disease treatment. Effective for increased cortisol. Consider 6 to 12 mg/kg, BID. See article on ketoconazole treatment in JAVMA, 233(12):1896 ... Jun 15, 2021 · Treatments will vary depending on the type of Cushing’s disease your dog has. Pituitary tumor. Treatment of pituitary dependent Cushing’s disease is the most complicated. Two drugs, trilostane and mitotane are commonly used. Adrenal tumor. Treatment of an adrenal dependent Cushing’s disease usually requires major abdominal surgery. The main indications for medical therapy of Cushing's syndrome include (see "Overview of the treatment of Cushing syndrome" ): Control of hypercortisolism in preparation for surgery – Although the hypercortisolism of Cushing's disease is optimally treated surgically, medical therapy is often required when surgery is delayed.Treatments will vary depending on the type of Cushing’s disease your dog has. Pituitary tumor. Treatment of pituitary dependent Cushing’s disease is the most complicated. Two drugs, trilostane and mitotane are commonly used. Adrenal tumor. Treatment of an adrenal dependent Cushing’s disease usually requires major abdominal surgery.Summary of Recommendations 1. Treatment goals for Cushing's syndrome. 1.1 In patients with overt Cushing's syndrome (CS), we recommend normalizing cortisol levels or action at its receptors to eliminate the signs and symptoms of CS and treating comorbidities associated with hypercortisolism.Treatment is typically pursued when the clinical signs start affecting a dog’s quality of life, and also when it’s necessary to reduce the complications associated with Cushing’s syndrome. It’s important to talk with your veterinarian about how to weigh the risks of surgery or the possible side effects of available medications. Cushing syndrome treatment Pituitary tumors. The most common type of treatment for pituitary tumors is surgery. The surgeon will go in through a... Ectopic ACTH-producing tumors. Like pituitary tumors, surgery is typically the first option for ectopic tumors. If... Adrenal tumors. Surgery to remove ...Treatment for Cushing's disease in dogs usually includes medications that help decrease the amount of cortisone that the adrenal glands produce. The only way to cure Cushing's disease is to remove the tumor, however, due to the complexity and risks of surgery, most cases are treated with medication. Treatments will vary based on the type of ...Recorlev (levoketoconazole, COR-003) Recorlev is a cortisol inhibitor that Strongbridge Biopharma (formerly Cortendo) is developing as a Cushing’s disease treatment. Both the FDA and the European Medicines Agency (EMA) have granted recorlev orphan drug status. A Phase 3 clinical trial called SONICS (NCT01838551) tested the treatment in ... The type of Cushing's disease may determine what kind of treatment is prescribed. Veterinarians use blood tests to diagnose Cushing's and to differentiate between disease caused by the pituitary ... Treatment of Cushing's Disease in Horses The first-line treatment for Cushing’s disease is an FDA-approved tablet called Prascend (pergolide). Some horses may need to be started on Prascend gradually as it can cause a decrease appetite.Common side effects of Cushing’s syndrome medications are unique to the mechanism of action of the medication. Speak with a healthcare provider about medication-specific side effects. Some well-known side effects include: Nausea, vomiting, and diarrhea. Headache and dizziness. Anxiety and depression.Treatments & Medication for Cushing’s Disease in Dogs. There are two main drugs used in the treatment of Cushing’s disease in dogs. A form of the insecticide DDT (drug names include Lysodren® and mitotane) can destroy the cells that produce cortisone in the adrenal glands. Other medications such as trilostane help decrease the amount of ...Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening ...Treatments will vary depending on the type of Cushing’s disease your dog has. Pituitary tumor. Treatment of pituitary dependent Cushing’s disease is the most complicated. Two drugs, trilostane and mitotane are commonly used. Adrenal tumor. Treatment of an adrenal dependent Cushing’s disease usually requires major abdominal surgery.Jul 6, 2021 · None of the treatments actually restore normal adrenal function but once the six months period has passed, dogs with the disease may live several more good quality years. New Developments: A new drug, trilostane, appears to have great potential in treating Cushing’s disease without some of the side effects caused by mitotane. Cushing’s Medication These treatments are meant to either reduce the levels of cortisol in the blood to normal levels or to shrink the size of pituitary or adrenal tumors. The most commonly prescribed drugs for Cushing’s disease are Mitotane and Trilostane (5) Mitotane is a human chemotherapy drug that is meant to shrink adrenal or ...Treatment for Cushing's Disease in dogs. As noted above, Cushing's Syndrome is due to a tumor growing in the pituitary or adrenal gland. Now it could be a benign or malignant tumor.Abstract. Cushing's disease (CD) is caused by a pituitary tumour that secretes adrenocorticotropin (ACTH) autonomously, leading to excess cortisol secretion from the adrenal glands. The condition is associated with increased morbidity and mortality that can be mitigated by treatments that result in sustained endocrine remission.Nov 3, 2017 · That said, 50% of the horses were alive 4.6 years after diagnosis (most that didn’t live got euthanized, and most of those got euthanzied because of problems related to Cushing’s). So, the bottom line is that you shouldn’t expect a treated horse to live longer with treatment, nor even to necessarily avoid problems. 10. Cushing’s disease is a debilitating disease, usually affecting geriatric dogs. Cushing’s happens due to a malfunction in your dog’s Endocrine System. Specifically, Cushing’s disease in dogs occurs when the dog’s adrenal glands overproduce Cortisol, also known as the “stress hormone”. The adrenal glands produce and store Cortisol.If a tumor is the cause of Cushing, treatments may include medication, surgery, radiation, chemotherapy, or a combination of these treatments. The treatment depends on the tumor’s location and type. Pituitary tumors. The most common treatments for pituitary tumors are: Surgery.PPID is caused by degeneration of neurons that affect the production of hormones such as adrenocorticotrophic hormone (ACTH). Common clinical signs include a long, curly hair coat, delayed shedding, loss of muscle, poor immune function, and laminitis. The only medication licensed for the treatment of PPID in horses is pergolide mesylate.What's the Treatment for Cushing's Disease in Dogs? Treatment of Cushing’s disease in dogs is largely dependent on the underlying cause. Treatment options include: Surgery. Medication. Radiation. If Cushing’s disease is caused by the excessive use of steroids, the steroid dosage should be carefully tapered down and discontinued.Recorlev (levoketoconazole, COR-003) Recorlev is a cortisol inhibitor that Strongbridge Biopharma (formerly Cortendo) is developing as a Cushing’s disease treatment. Both the FDA and the European Medicines Agency (EMA) have granted recorlev orphan drug status. A Phase 3 clinical trial called SONICS (NCT01838551) tested the treatment in ...Jan 18, 2022 · Natural Treatments for Canine Cushing’s. In addition to a good diet, your dog may benefit from a few herbs and supplements that are proving to help with this condition. Cushing’s is a complicated disease, and you may have to experiment a bit in order to get the best treatment for your dog. Recorlev (levoketoconazole, COR-003) Recorlev is a cortisol inhibitor that Strongbridge Biopharma (formerly Cortendo) is developing as a Cushing’s disease treatment. Both the FDA and the European Medicines Agency (EMA) have granted recorlev orphan drug status. A Phase 3 clinical trial called SONICS (NCT01838551) tested the treatment in ...May 21, 2021 · Treatment of Cushing’s Disease. The location of the tumor dictates which treatment to use. More than 90 percent of dogs with CD have a pituitary-gland tumor. This type of tumor is only ... Best Cushing’s Disease Treatment For Horses. The most common and effective treatment for Cushing’s disease is a drug called pergolide mesylate. Your veterinarian may also refer to this drug as Prascend®. Pergolide comes in tablet form and is given once per day. It works by reducing the high levels of ACTH.Treatments. If Cushing’s syndrome comes from a tumor on your pet’s adrenal glands, the vet might be able to remove it with surgery, which will cure him of the problem. But if the tumor has ... The main indications for medical therapy of Cushing's syndrome include (see "Overview of the treatment of Cushing syndrome" ): Control of hypercortisolism in preparation for surgery – Although the hypercortisolism of Cushing's disease is optimally treated surgically, medical therapy is often required when surgery is delayed.Aug 19, 2015 · The Endocrine Society recommends that the first-line treatment for endogenous Cushing’s syndrome be the removal of the tumor unless surgery is not possible or unlikely to address the excess cortisol. Surgical removal of the tumor is optimal because it leaves intact the hypothalamic-pituitary-adrenal axis, which is integral to the body’s ... Abstract. Cushing's disease (CD) is caused by a pituitary tumour that secretes adrenocorticotropin (ACTH) autonomously, leading to excess cortisol secretion from the adrenal glands. The condition is associated with increased morbidity and mortality that can be mitigated by treatments that result in sustained endocrine remission.Treatment for Cushing's syndrome. Cushing's syndrome usually gets better with treatment, although it might take a long time to recover completely. Treatment depends on what's causing it. If it's caused by taking steroids: your steroid dose will be gradually reduced or stopped; If it's caused by a tumour, treatment may include: surgery to remove ... That said, 50% of the horses were alive 4.6 years after diagnosis (most that didn’t live got euthanized, and most of those got euthanzied because of problems related to Cushing’s). So, the bottom line is that you shouldn’t expect a treated horse to live longer with treatment, nor even to necessarily avoid problems. 10.III. The First-line Treatment of Cushing's Disease. The main objectives for the treatment of CD include: 1) normalization of cortisol secretion; 2) reversal of the clinical picture; 3) prevention or recovery of the concomitant comorbidities and clinical complications; and 4) long-term disease control without disease recurrence (1, 2, 7, 84 ...Treatment for Cushing's syndrome should happen as soon as possible. Complications of the disease are serious. If left untreated, it can cause bone loss and fractures, muscle loss and high blood pressure. It can also cause Type 2 diabetes, kidney stones and infections. Recovery from Cushing's syndrome Jan 28, 2021 · Treatment for Cushing's disease in dogs usually includes medications that help decrease the amount of cortisone that the adrenal glands produce. The only way to cure Cushing's disease is to remove the tumor, however, due to the complexity and risks of surgery, most cases are treated with medication. Treatments will vary based on the type of ... Endocrine System What is Cushing's syndrome? Cushing's syndrome is a hormonal disorder. It’s caused when you have high levels of the hormone cortisol over a long time. Cushing's syndrome is fairly rare. It most often affects adults who are 20 to 50 years old. It is sometimes called hypercortisolism.Other causes include tumors that make the body produce excess cortisol. Cushing syndrome includes a range of treatable symptoms. In most cases, the syndrome is curable. NICHD is one of the many federal agencies that support and conduct research on the causes of Cushing syndrome, ways to diagnose it earlier, and better treatments.Oct 20, 2021 · Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening ... Melatonin for dogs with Cushings. Melatonin can be effective in the treatment of Cushing’s because it inhibits two enzymes needed in the production of cortisol. By inhibiting the enzymes, cortisol levels can be reduced. It is important to use the right kind of melatonin and to keep melatonin in the body at a constant level. None of the medications can cure Cushing’s, so they are usually taken until other treatments are given to cure Cushing’s, and only after that if the other treatment fails. The most common treatment for Cushing’s disease is transsphenoidal surgery, which requires the surgeon to reach the pituitary gland through the nostril or upper lip and ...adequate time for either drug’s effects on the adrenals to subside before switching treatments. (E.g., one month off drug; normal or increased stimulation-cortisol levels). 8) Ketoconazole. Cushing’s disease treatment. Effective for increased cortisol. Consider 6 to 12 mg/kg, BID. See article on ketoconazole treatment in JAVMA, 233(12):1896 ... Summary of Recommendations 1. Treatment goals for Cushing's syndrome. 1.1 In patients with overt Cushing's syndrome (CS), we recommend normalizing cortisol levels or action at its receptors to eliminate the signs and symptoms of CS and treating comorbidities associated with hypercortisolism.Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening ...Surgery - If your dog's Cushing's disease was caused by a tumor, surgery might be an option. Only your vet is qualified to consult with about this option. 3-beta-hydroxysteroid-dehydrogenase drugs - These drugs have been shown to be an effective treatment for canine and feline Cushing’s syndrome. These are a synthetic, orally active steroid ...Top 7 Best Treatment for Cushings in Horses. Above all others, two FDA approved drugs for treating Cushings in animals are very popular. They are Trilostane (Vetoryl) and Mitotane (Lysodren). Mitotane is quite old, and most veterinarians don’t prescribe it anymore.Lifestyle and home remedies Increase activities slowly. Work up to a comfortable level of exercise or activity without overdoing it. Don't do... Eat sensibly. Nutritious foods are a good source of fuel for your body during recovery. They also can help you lose any... Keep an eye on your mental ...Mar 3, 2017 · If a tumor is the cause of Cushing, treatments may include medication, surgery, radiation, chemotherapy, or a combination of these treatments. The treatment depends on the tumor’s location and type. Pituitary tumors. The most common treatments for pituitary tumors are: Surgery. Cushing’s horses today have a better prognosis than ever before, and with proper treatment and management they can enjoy long and productive lives. In recent studies, McFarlane has found that PPID begins when hypothalamic neurons degenerate and produce less dopamine, the substance that restrains pituitary secretion.Treatment Goal: Bring cortisol back to normal. When treating Cushing's disease, surgery is the recommended first choice of treatment to bring cortisol levels back to normal. This is a specific surgery to remove the pituitary gland tumor. However, if you are unable to have surgery or choose not to, there are medications to help lower cortisol ...Endocrine System What is Cushing's syndrome? Cushing's syndrome is a hormonal disorder. It’s caused when you have high levels of the hormone cortisol over a long time. Cushing's syndrome is fairly rare. It most often affects adults who are 20 to 50 years old. It is sometimes called hypercortisolism.Oct 12, 2022 · Treatment of Cushing syndrome is directed by the primary cause of the syndrome. In general, therapy should reduce the cortisol secretion to normal to reduce the risk of comorbidities associated with hypercortisolism. The treatment of choice for endogenous Cushing syndrome is surgical resection of the causative tumor. Other symptoms of Cushing's Disease in Horses: Excessive drinking and urination. Non-specific laminitis. A tendency for recurring infections in the hoof (foot abscesses) Loss of muscle mass, especially along the topline and rump. Depression and/or lack of energy. Fatty deposits, including cresty neck and/or weight loss.May 18, 2023 · Top 7 Best Treatment for Cushings in Horses. Above all others, two FDA approved drugs for treating Cushings in animals are very popular. They are Trilostane (Vetoryl) and Mitotane (Lysodren). Mitotane is quite old, and most veterinarians don’t prescribe it anymore. Melatonin for dogs with Cushings. Melatonin can be effective in the treatment of Cushing’s because it inhibits two enzymes needed in the production of cortisol. By inhibiting the enzymes, cortisol levels can be reduced. It is important to use the right kind of melatonin and to keep melatonin in the body at a constant level.Treatments & Medication for Cushing’s Disease in Dogs. There are two main drugs used in the treatment of Cushing’s disease in dogs. A form of the insecticide DDT (drug names include Lysodren® and mitotane) can destroy the cells that produce cortisone in the adrenal glands. Other medications such as trilostane help decrease the amount of ...Cushing's syndrome is a disorder caused by the body’s exposure to an excess of the hormone cortisol. Cortisol affects all tissues and organs in the body. These effects together are known as Cushing's syndrome. Cushing’s syndrome can be caused by overuse of cortisol medication, as seen in the treatment of chronic asthma or rheumatoid ...Sep 22, 2020 · Cushing’s syndrome is a very “stressful” disease to contract, but there are many natural remedies for this condition, including sleeping more, reducing stress, exercising regularly, altering your diet, and using herbal treatments, among others. These treatments might be the only option for people with Cushing’s disease that has progressed, but for others with Cushing’s syndrome or just symptoms of high cortisol, lifestyle changes can ...Begin long term mitotane treatment. Mitotane treatment is lifelong. Long term mitotane treatment is usually once or twice weekly. Unfortunately, for some dogs, Cushing’s disease symptoms come back during long term mitotane treatment. If this happens to your dog, it will need to go back to daily mitotane.adequate time for either drug’s effects on the adrenals to subside before switching treatments. (E.g., one month off drug; normal or increased stimulation-cortisol levels). 8) Ketoconazole. Cushing’s disease treatment. Effective for increased cortisol. Consider 6 to 12 mg/kg, BID. See article on ketoconazole treatment in JAVMA, 233(12):1896 ... Eastern herbals and dietary therapy is The way I treat pretty much all Cushing’s. The typical Western treatment with vetoryl I pretty much reserved for the most aggressive forms of Cushing’s. Other treatments you might be interested in for atypical Cushing’s include melatonin and lignan therapy. Thank you and I hope this helps. Daphne:Cushing’s disease is a progressive disorder in which there is an excess of cortisol in the body. While the disease can be treated surgically, this option is not possible for all patients. Following are currently approved medication treatments that assist in controling cortisol levels in individuals with Cushing’s disease. That said, 50% of the horses were alive 4.6 years after diagnosis (most that didn’t live got euthanized, and most of those got euthanzied because of problems related to Cushing’s). So, the bottom line is that you shouldn’t expect a treated horse to live longer with treatment, nor even to necessarily avoid problems. 10.The Leptin Connection. Cushing’s disease, which causes a constant fight-or-flight state of elevated cortisol, forces the body to store loads of fat to protect the organs. “People often gain 100 pounds. I was lucky to gain a little over 30, but as a trainer that can end your career,” says Lombard.Treatment Goal: Bring cortisol back to normal. When treating Cushing's disease, surgery is the recommended first choice of treatment to bring cortisol levels back to normal. This is a specific surgery to remove the pituitary gland tumor. However, if you are unable to have surgery or choose not to, there are medications to help lower cortisol ...
Endogenous Cushing’s syndrome is a grave disease that requires a multidisciplinary and individualized treatment approach for each patient. Approximately 80% of all patients harbour a corticotroph pituitary adenoma (Cushing’s disease) with excessive secretion of adrenocorticotropin-hormone (ACTH) and, consecutively, cortisol.. Kands tire
Treatment of Cushing’s Disease. The location of the tumor dictates which treatment to use. More than 90 percent of dogs with CD have a pituitary-gland tumor. This type of tumor is only ...Treatments. If Cushing’s syndrome comes from a tumor on your pet’s adrenal glands, the vet might be able to remove it with surgery, which will cure him of the problem. But if the tumor has ... None of the medications can cure Cushing’s, so they are usually taken until other treatments are given to cure Cushing’s, and only after that if the other treatment fails. The most common treatment for Cushing’s disease is transsphenoidal surgery, which requires the surgeon to reach the pituitary gland through the nostril or upper lip and ...The optimal treatment for Cushing’s disease depends on a patient’s particular clinical situation, the severity of the symptoms, and the characteristics of the underlying pituitary tumor that causes the condition. Usually the first line treatment for Cushing’s disease is the surgical removal of the pituitary tumor — a procedure called ...May 21, 2021 · Treatment of Cushing’s Disease. The location of the tumor dictates which treatment to use. More than 90 percent of dogs with CD have a pituitary-gland tumor. This type of tumor is only ... There are treatments for Cushing syndrome. Treatment may last for some time. Symptoms and Causes Diagnosis and Tests Management and Treatment Prevention Outlook / Prognosis Living With Overview What is Cushing syndrome? Cushing syndrome is an uncommon condition that happens when your body has too much of a hormone called cortisol.Treatment for Cushing's Disease in dogs. As noted above, Cushing's Syndrome is due to a tumor growing in the pituitary or adrenal gland. Now it could be a benign or malignant tumor.Cushing Syndrome is a hormonal disorder caused by high levels of the hormone cortisol in the body. Find top treatment options, what causes it and more.These treatments might be the only option for people with Cushing’s disease that has progressed, but for others with Cushing’s syndrome or just symptoms of high cortisol, lifestyle changes can ...Treatments. Treatment for Cushing's syndrome depends on the specific reason for cortisol excess and may include surgery, radiation, chemotherapy or the use of cortisol-inhibiting drugs. Surgery Surgery typically involves transsphenoidal removal of the adenoma. It is one of the primary treatment method used to achieve a long-term cure of Cushing ... Endocrine System What is Cushing's syndrome? Cushing's syndrome is a hormonal disorder. It’s caused when you have high levels of the hormone cortisol over a long time. Cushing's syndrome is fairly rare. It most often affects adults who are 20 to 50 years old. It is sometimes called hypercortisolism.Recorlev (levoketoconazole, COR-003) Recorlev is a cortisol inhibitor that Strongbridge Biopharma (formerly Cortendo) is developing as a Cushing’s disease treatment. Both the FDA and the European Medicines Agency (EMA) have granted recorlev orphan drug status. A Phase 3 clinical trial called SONICS (NCT01838551) tested the treatment in ... .