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Conclusionsنتیجه

Crohn"s disease is a chronic inflammatory disease involving predominantly the small intestine and colon. The symptoms and the activity of the disease can come and go. Even though many effective medications are available to control the activity of the disease, there is as yet no cure for Crohn"s disease. Surgery can significantly improve the quality of life in selected individuals, but recurrence of the disease after surgery is common. The disease can have complications, both within and outside of the intestine. Newer treatments are actively being evaluated. A better understanding of the role of genetics and environmental factors in the cause of Crohn"s disease may lead to improved treatments and prevention of the disease.

Crohn"s Disease At A Glance کرون در یک نگاه

• Crohn"s disease is a chronic inflammatory disease of the intestines.
• The cause of Crohn"s disease is unknown.
• Crohn"s disease can cause ulcers in the small intestine, colon, or both.
• Abdominal pain, diarrhea, vomiting, fever, and weight loss are symptoms of Crohn"s disease.
• Crohn"s disease of the small intestine may cause obstruction of the intestine.
• Crohn"s disease can be associated with reddish, tender skin nodules, and inflammation of the joints, spine, eyes, and liver.
• The diagnosis of Crohn"s disease is made by barium enema, barium x-ray of the small bowel, and colonoscopy.
• The choice of treatment for Crohn"s disease depends on the location and severity of the disease.
• Treatment of Crohn"s disease includes drugs for suppressing inflammation or the immune system, antibiotics, and surgery.

Infliximab (Remicade)

Infliximab (Remicade) is an antibody that attaches to a protein called tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is one of the proteins produced by immune cells during activation of the immune system. TNF-alpha, in turn, stimulates other cells of the immune system to produce and release other proteins that promote inflammation. In Crohn"s disease, there is continued production of TNF-alpha as part of the immune activation. Infliximab, by attaching to TNF-alpha, blocks its activity and in so doing decreases the inflammation.

Infliximab, an antibody to TNF-alpha, is produced by the immune system of mice after the mice are injected with human TNF-alpha. The mouse antibody then is modified to make it look more like a human antibody, and this modified antibody is infliximab. Such modifications are necessary to decrease the likelihood of allergic reactions when the antibody is administered to humans. Infliximab is given by intravenous infusion over two hours. Patients are monitored throughout the infusion for adverse reactions.

In August 1998 the United States Food and Drug Administration approved the use of infliximab for the short-term treatment of moderate to severe Crohn"s disease patients who respond inadequately to corticosteroids, azathioprine, or 6-MP.

Effectiveness of infliximab

Infliximab is an effective and fast-acting drug for the treatment of active Crohn"s disease. In a study involving patients with moderate to severe Crohn"s disease who were not responding to corticosteroids or immuno-modulators, 65% experienced improvement in their disease after one infusion of infliximab. Some patients noticed improvement in symptoms within days of the infusion. Most patients experienced improvement within two weeks.

In patients who respond to infliximab, the improvements in symptoms can be dramatic. Moreover, there can be impressively rapid healing of the ulcers and the inflammation in the intestines after just one infusion.

The anal fistulae of Crohn"s disease are troublesome and often difficult to treat. Infliximab has been found to be effective for treating fistulae.

Duration of benefits with infliximab

The majority of the patients who responded to a first infusion of infliximab developed recurrence of their disease within three months. However, studies have shown that repeated infusions of infliximab every eight weeks are safe and effective in maintaining remission in many patients over a one to two year period. Response to infliximab after repeated infusions sometimes is lost if the patient starts to develop antibodies to the infliximab (which attach to the infliximab and prevent it from working). Studies are now being done to determine the long-term safety and effectiveness of repeated infusions of infliximab.

One potential use of infliximab is to quickly control active and severe disease. The use of infliximab then may be followed by maintenance treatment with azathioprine, 6-MP or 5-ASA compounds. Azathioprine or 6-MP also may be helpful in preventing the development of antibodies against infliximab.

Side effects of infliximab

Infliximab generally is well-tolerated. There have been rare reports of side effects during infusions, including chest pain, shortness of breath, and nausea. These effects usually resolve spontaneously within minutes if the infusion is stopped. Other commonly-reported side effects include headache and upper respiratory tract infection.

TNF-alpha is an important protein for defending the body against infections. Infliximab, like immuno-modulators, increases the risk for infection. One case of salmonella colitis and several cases of pneumonia have been reported with the use of infliximab. There also have been cases of tuberculosis (TB) reported after the use of infliximab.

Because infliximab is partly a mouse protein, it may induce an immune reaction when given to humans, especially with repeated infusions. In addition to the side effects that occur while the infusion is being given, patients also may develop a "delayed allergic reaction" that occurs 7-10 days after receiving the infliximab. This type of reaction may cause flu-like symptoms with fever, joint pain and swelling, and a worsening of Crohn"s disease symptoms. It can be serious, and if it occurs, a physician should be contacted. Paradoxically, those patients who have more frequent infusions of infliximab are less likely to develop this type of delayed reaction compared to those patients who receive infusions separated by long intervals (6-12 months). Although infliximab is only FDA approved for a single infusion at this time, patients should be aware that they are likely to require repeated infusions once Remicade therapy has been initiated.

Rare cases of nerve inflammation such as optic neuritis (inflammation of the nerve of the eye) and mother neuropathy has been reported with the use of infliximab.

Precautions with infliximab

Infliximab can aggravate and cause the spread of an existing infection. Therefore, it should not be given to patients with pneumonia, urinary tract infection or abscess (localized collection of pus). It now is recommended that patients be tested for TB prior to receiving infliximab. Patients who previously had TB should inform their physician of this before they receive infliximab infliximab can cause the spread of cancer cells; therefore, it should not be given to patients with cancer.

Infliximab can promote intestinal scarring (part of the process of healing) and, therefore, can worsen strictures (narrowed areas of the intestine caused by inflammation and subsequent scaring) and lead to intestinal obstruction. It also can cause partial healing (partial closure) of anal fistulae. Partial closure of fistulae impedes drainage of fluid through the fistulae, and may result in collections of fluid in which bacteria multiply, which can result in abscesses.

The effects infliximab on the fetus are not known.

Because infliximab is partly a mouse protein, some patients can develop antibodies against infliximab with repeated infusions. Such antibodies can decrease the effectiveness of the drug. The chance of developing such antibodies can be decreased by the concomitant use of 6-MP and corticosteroids. There are some reports of worsening heart disease in patients who have received Remicade. The precise mechanism and role of infliximab in the development of this side effect is unclear. As a precaution, individuals with heart disease should inform their physician of this condition before receiving infliximab.

While infliximab represents an exciting new class of medications in the fight against Crohn"s disease, caution is warranted in its use. The long-term safety and effectiveness is not yet known

GENERIC NAME: budesonide

BRAND NAME: Entocort EC

DRUG CLASS AND MECHANISM: Budesonide is a synthetic steroid of the glucocorticoid family. The naturally-occurring hormone whose actions budesonide mimics, is cortisol or hydrocortisone which is produced by the adrenal glands. Glucocorticoid steroids have potent anti-inflammatory actions. Crohn"s disease is a chronic inflammatory bowel disease of unknown cause that results in diarrhea, crampy abdominal pain, fever and bleeding from the rectum. The active ingredient in Entocort EC, budesonide, is released from granules in the ileum of the small intestine and the right (proximal) colon, where the inflammation of Crohn"s disease occurs. Budesonide acts directly by contact with the ileum and colon. The budesonide that is absorbed into the body travels to the liver where it is broken-down and eliminated from the body. This prevents the majority of the absorbed drug from being distributed to the rest of the body. As a result, budesonide causes fewer severe side effects throughout the body than other corticosteroids. The FDA approved Entocort EC in October of 2001.

PREION: Yes

GENERIC AVAILABLE: No

PREPARATIONS: Capsules: 3mg

STORAGE: Capsules should be stored between 15-30°C (59-86°F)

PRESCRIBED FOR: Budesonide is used for the treatment of mild-to-moderately-active Crohn"s disease involving the ileum (the second half of the small intestine) and/or ascending colon (the beginning of the large intestine).  It also is approved for maintaining remissions for up to three months.

DOSING: Budesonide usually is taken once daily for up to eight weeks.

DRUG INTERACTIONS: Medicines which block the liver enzymes that break down budesonide may lead to higher blood concentrations and more side effects. Such medications include ketoconazole (Nizoral), fluconazole (Diflucan), itraconazole (Sporanox), clarithromycin (Biaxin), erythromycin, verapamil (e.g. Calan; Isoptin; Covera HS), diltiazem (e.g. Cardizem; Dilacor), ritonavir (Norvir; Kaletra), indinavir (Crixivan), and saquinavir (Invirase, Fortovase). Grapefruit juice has the same effect and should not be drunk by patients taking budesonide.

PREGNANCY: Glucocorticoids taken orally that are similar to budesonide have been shown to cause fetal abnormalities in animals. It is not known if there is an increased risk of malformation in children born to mothers exposed to budesonide during pregnancy.

NURSING MOTHERS: Glucocorticosteroids are secreted in human milk. Because of the potential for adverse reactions in nursing infants from any corticosteroid, a decision should be made whether to discontinue nursing or discontinue the budesonide. The amount of budesonide secreted in breast milk has not been determined.

SIDE EFFECTS: Budesonide generally is well tolerated. The most common side effects are headache (1 in 5 patients), respiratory infection (1 in 10 patients), nausea (1 in 10 patients), and symptoms or signs of too much corticosteroid. In the latter case, acne occurs in about 1 in 6 patients, easy bruising in 1 in 6 patients, moon (rounded) faces in 1 in 10 patients, and swollen ankles in 1 in 14 patients.

High doses of glucocorticoids may decrease the formation and increase the breakdown of bone. Higher doses also may suppress the body"s ability to make its own natural glucocorticoid, cortisol. It is possible that these effects are shared by budesonide. People with suppressed production of cortisol (which can be tested for by the doctor) need increased amounts of glucocorticoids, probably by the oral or intravenous route during periods of high physical stress.

Pharmacy Author: Emmanuel Saltiel, Pharm.D.
Medical Editor: Jay W. Marks, M.D.

Budesonide (Entocort EC)

Budesonide (Entocort EC) is a new type of corticosteroid for treating Crohn"s disease. Like other corticosteroids, budesonide is a potent antiinflammatory medication. Unlike other corticosteroids, however, budesonide acts only via direct contact with the inflamed tissues (topically) and not systemically. As soon as budesonide is absorbed into the body, the liver converts it into inactive chemicals. Therefore, for effective treatment of Crohn"s disease, budesonide, like topical 5-ASA, must be brought into direct contact with the inflamed intestinal tissue.

Budesonide capsules contain granules that allow a slow release of the drug into the ileum and the colon. In a double-blind multicenter study (published in 1998), 182 patients with Crohn"s ileitis and/or Crohn"s disease of the right colon were treated with either budesonide (9 mg daily) or Pentasa (2 grams twice daily). Budesonide was more effective than Pentasa in inducing remissions while the side effects were similar to Pentasa. In another study comparing the effectiveness of budesonide with corticosteroids, budesonide was not better than corticosteroids in treating Crohn"s disease but had fewer side effects.

Because budesonide is broken down by the liver into inactive chemicals, it has fewer side effects than systemic corticosteroids. It also suppresses the adrenal glands less than systemic corticosteroids. Budesonide will be available as an enema for the treatment of proctitis.

Budesonide has not been shown to be effective in maintaining remission in patients with Crohn"s disease. If used long-term, budesonide also may cause some of the same side effects as corticosteroids. Because of this, the use of budesonide should be limited to short-term treatment for inducing remission. Most budesonide is released in the terminal ileum, it will have its best results in Crohn"s disease limited to the terminal ileum.

It is not known whether budesonide is effective in treating patients with ulcerative colitis, and it is currently not recommended for the treatment of ulcerative colitis.

Antibiotics for Crohn"s disease

Antibiotics such as metronidazole (Flagyl) and ciprofloxacin (Cipro) have been used for treating Crohn"s colitis. Flagyl also has been useful in treating anal fistulae in patients with Crohn"s disease. The mechanism of action of these antibiotics in Crohn"s disease is not well understood.

Metronidazole (Flagyl)

Metronidazole (Flagyl) is an antibiotic that is used for treating several infections caused by parasites (for example, giardia) and bacteria (for example, infections caused by anaerobic bacteria, and vaginal infections). It is effective in treating Crohn"s colitis and is particularly useful in treating patients with anal fistulae. Chronic use of metronidazole in doses higher than 1 gram daily can be associated with permanent nerve damage (peripheral neuropathy). The early symptoms of peripheral neuropathy are numbness and tingling in the fingertips, toes, and other parts of the extremities. Metronidazole should be stopped promptly if these symptoms appear. Metronidazole and alcohol together can cause severe nausea, vomiting, cramps, flushing, and headache. Patients taking metronidazole should avoid alcohol. Other side effects of metronidazole include nausea, headaches, loss of appetite, a metallic taste, and, rarely, a rash.

Ciprofloxacin (Cipro)

Ciprofloxacin (Cipro) is another antibiotic used in the treatment of Crohn"s disease. It can be used in combination with metronidazole.

Summary of antiinflammatory medicationsنگرش اجمالی  از داروهای ضد التهابی  تجویزی در بیماری کرون

• Azulfidine, Asacol, Pentasa, Dipentum, Colazal and Rowasa all contain 5-ASA which is the active topical antiinflammatory ingredient. Azulfidine was the first 5-ASA medication used in treating ulcerative colitis and Crohn"s disease, but the newer 5-ASA medications have fewer side effects.
• Pentasa and Asacol have been found to be effective in treating patients with Crohn"s ileitis and ileo-colitis. Rowasa enemas and Canasa suppositories are safe and effective for treating patients with proctitis. For mild to moderate Crohn"s ileitis or ileo-colitis, doctors usually start with Pentasa or Asacol. If Pentasa or Asacol is ineffective, doctors may try antibiotics such as Cipro or Flagyl for prolonged periods (often months).
• In patients with moderate to severe disease and in patients who fail to respond to 5-ASA compounds and/or antibiotics, systemic corticosteroids can be used. Systemic corticosteroids are potent and fast-acting antiinflammatory agents for treating Crohn"s enteritis and colitis as well as ulcerative colitis.
• Systemic corticosteroids are not effective in maintaining remission in patients with Crohn"s disease. Serious side effects can result from prolonged corticosteroid treatment.
• To minimize side effects, corticosteroids should be gradually tapered as soon as a remission is achieved. In patients who become corticosteroid dependent or are unresponsive to corticosteroid treatment, surgery or immuno-modulator treatment are considered.
• A new class of topical corticosteroids (budesonide) may have fewer side effects than systemic corticosteroids

How is Crohn"s disease diagnosedبیماری کرون چگونه   تشخیص داده میشود

The diagnosis of Crohn"s disease is suspected in patients with fever, abdominal pain and tenderness, diarrhea with or without bleeding, and anal diseases. Laboratory blood tests may show elevated white cell counts and sedimentation rates, both of which suggest infection or inflammation. Other blood tests may show low red blood cell counts (anemia), low blood proteins, and low body minerals, reflecting loss of these elements due to chronic diarrhea.

Barium x-ray studies can be used to define the distribution, nature, and severity of the disease. Barium is a chalky material that is visible by x-ray and appears white on x-ray films. When barium is ingested orally (upper GI series) it fills the intestine and pictures (x-rays) can be taken of the stomach and the small intestines. When barium is administered through the rectum (barium enema), pictures of the colon and the terminal ileum can be obtained. Barium x-rays can show ulcerations, narrowing, and, sometimes, fistulae of the bowel.

Direct visualization of the rectum and the large intestine can be accomplished with flexible viewing tubes (colonoscopes). Colonoscopy is more accurate than barium x-rays in detecting small ulcers or small areas of inflammation of the colon and terminal ileum. Colonoscopy also allows for small tissue samples (biopsies) to be taken and sent for examination under the microscope to confirm the diagnosis of Crohn"s disease. Colonoscopy also is more accurate than barium x-rays in assessing the degree (activity) of inflammation.

Computerized axial tomography (CAT or CT) scanning is a computerized x-ray technique that allows imaging of the entire abdomen and pelvis. It can be especially helpful in detecting abscesses.

Most recently, video capsule endoscopy has been added to the list of diagnostic tests for diagnosing Crohn"s disease. For video capsule endoscopy, a capsule containing a miniature video camera is swallowed. As the capsule travels through the small intestine, it sends video images of the lining of the small intestine to a receiver carried on a belt at the waist. The images are downloaded and then reviewed on a computer. The value of video capsule endoscopy is that it can identify the early, mild abnormalities of Crohn"s disease. Video capsule endoscopy may be particularly useful when there is a strong suspicion of Crohn"s disease but the barium x-rays are normal. (Barium x-rays are not as good at identifying early, mild Crohn"s disease.)

Video capsule endoscopy should not be performed in patients who have obstruction of the small intestine. The capsule may get stuck behind the obstruction and make the obstruction worse. Doctors usually also are reluctant to perform video-capsule endoscopy for the same reason in patients who they suspect of having small intestinal strictures (narrowed segments of small intestine that can result from prior surgery, prior radiation, or chronic ulceration, for example, from Crohn"s disease). There is also a theoretical concern for electrical interference between the capsule and implanted cardiac pacemakers and defibrillators; however, so far in a small number of patients with pacemakers or defibrillators who have undergone video capsule endoscopy there have been no problems.

How does Crohn"s disease affect the intestines?اثرات کرون بر روده  ها  

In the early stages, Crohn"s disease causes small, scattered, shallow, crater-like areas (erosions) on the inner surface of the bowel. These erosions are called aphthous ulcers. With time, the erosions become deeper and larger, ultimately becoming true ulcers (which are deeper than erosions) and causing scarring and stiffness of the bowel. As the disease progresses, the bowel becomes increasingly narrowed, and ultimately can become obstructed. Deep ulcers can puncture holes in the wall of the bowel, and bacteria from within the bowel can spread to infect adjacent organs and the surrounding abdominal cavity.

When Crohn"s disease narrows the small intestine to the point of obstruction, the flow of the contents through the intestine ceases. Sometimes, the obstruction can be caused suddenly by poorly-digestible fruit or vegetables that plug the already-narrowed segment of the intestine. When the intestine is obstructed, digesting food, fluid and gas from the stomach and the small intestine cannot pass into the colon. The symptoms of small intestinal obstruction then appear, including severe abdominal cramps, nausea, vomiting, and abdominal distention. Obstruction of the small intestine is much more likely since the small intestine is much narrower than the colon to begin with.

Deep ulcers can puncture holes in the walls of the small intestine and the colon, and create a tunnel between the intestine and adjacent organs. If the ulcer tunnel reaches an adjacent empty space inside the abdominal cavity, a collection of infected pus (an abdominal abscess) is formed. Patients with abdominal abscesses can develop tender abdominal masses, high fevers, and abdominal pain.

When the ulcer tunnels into an adjacent organ, a channel (fistula) is formed. The formation of a fistula between the intestine and the bladder (enteric-vesicular fistula) can cause frequent urinary tract infections and the passage of gas and feces during urination. When a fistula develops between the intestine and the skin (enteric-cutaneous fistula), pus and mucous emerge from a small painful opening on the skin of the abdomen. The development of a fistula between the colon and the vagina (colonic-vaginal fistula) causes gas and feces to emerge through the vagina. The presence of a fistula from the intestines to the anus (anal fistula) leads to a discharge of mucous and pus from the fistula"s opening around the anus.

How is Crohn"s disease different from ulcerative colitis? تشخیص کرون از کولیت  زخمی

While ulcerative colitis causes inflammation only in the colon (colitis) and/or the rectum (proctitis), Crohn"s disease may cause inflammation in the colon, rectum, small intestine (jejunum and ileum), and, occasionally, even the stomach, mouth, and esophagus.

The patterns of inflammation in Crohn"s disease are different from ulcerative colitis. Except in the most severe cases, the inflammation of ulcerative colitis tends to involve the superficial layers of the inner lining of the bowel. The inflammation also tends to be diffuse and uniform. (All of the lining in the affected segment of the intestine is inflamed.) Unlike ulcerative colitis, the inflammation of Crohn"s disease is concentrated in some areas more than others and involves layers of the bowel that are deeper than the superficial inner layers. Therefore, the affected segment(s) of bowel in Crohn"s disease often is studded with deeper ulcers with normal lining between these ulcers.

What are the symptoms of Crohn"s disease?  

نشانه های انواع  بیماری کرون               

Common symptoms of Crohn"s disease include abdominal pain, diarrhea, and weight loss. Less common symptoms include poor appetite, fever, night sweats, rectal pain, and rectal bleeding. The symptoms of Crohn"s disease are dependent on the location, the extent, and the severity of the inflammation. The different subtypes of Crohn"s disease and their symptoms are:

1. Crohn"s colitis is inflammation that is confined to the colon. Abdominal pain and bloody diarrhea are the common symptoms. Anal fistulae and peri-rectal abscesses also can occur.

2. Crohn"s enteritis refers to inflammation confined to the small intestine (the first part, called the jejunum or the second part, called the ileum). Involvement of the ileum alone is referred to as Crohn"s ileitis. Abdominal pain and diarrhea are the common symptoms. Obstruction of the small intestine also can occur.

3. Crohn"s terminal ileitis is inflammation that affects only the very end of the small intestine (terminal ileum), the part of the small intestine closest to the colon. Abdominal pain and diarrhea are the common symptoms. Small intestinal obstruction also can occur.

4. Crohn"s entero-colitis and ileo-colitis are terms to describe inflammation that involve both the small intestine and the colon. Bloody diarrhea and abdominal pain are the common symptoms. Small intestinal obstruction also can occur.

Crohn"s terminal ileitis and ileo-colitis are the most common types of Crohn"s disease. (Ulcerative colitis frequently involves only the rectum or rectum and sigmoid colon at the distal end of the colon. These are called ulcerative proctitis and procto-sigmoiditis, respectively.)

Up to one third of patients with Crohn"s disease may have one or more of the following conditions involving the anal area:

1. Swelling of the tissue of the anal sphincter, the muscle at the end of the colon that controls defecation.

2. Development of ulcers and fissures (long ulcers) within the anal sphincter. These ulcers and fissures can cause bleeding and pain with defecation.

3. Development of anal fistulae (abnormal tunnels) between the anus or rectum and the skin surrounding the anus). Mucous and pus may drain from the openings of the fistulae on the skin.

4. Development of peri-rectal abscesses (collections of pus in the anal and rectal area). Peri-rectal abscesses can cause fever, pain and tenderness around the anus.

What is Crohn"s disease?

Crohn"s disease is a chronic inflammatory disease of the intestines. It primarily causes ulcerations (breaks in the lining) of the small and large intestines, but can affect the digestive system anywhere from the mouth to the anus. It is named after the physician who described the disease in 1932. It also is called granulomatous enteritis or colitis, regional enteritis, ileitis, or terminal ileitis.

Crohn"s disease is related closely to another chronic inflammatory condition that involves only the colon called ulcerative colitis. Together, Crohn"s disease and ulcerative colitis are frequently referred to as inflammatory bowel disease (IBD). Ulcerative colitis and Crohn"s disease have no medical cure. Once the diseases begin, they tend to fluctuate between periods of inactivity (remission) and activity (relapse). They affect approximately 500,000 to two million people in the United States. Men and women are equally affected. IBD most commonly begins during adolescence and early adulthood, but it also can begin during childhood and later in life.

Crohn"s disease tends to be more common in relatives of patients with Crohn"s disease. It also is more common among relatives of patients with ulcerative colitis.

What causes Crohn"s disease?

The cause of Crohn"s disease is unknown. Some scientists suspect that infection by certain bacteria, such as strains of mycobacterium, may be the cause of Crohn"s disease. To date, however, there has been no convincing evidence that the disease is caused by infection. Crohn"s disease is not contagious. Although diet may affect the symptoms in patients with Crohn"s disease, it is unlikely that diet is responsible for the disease.

Activation of the immune system in the intestines appears to be important in IBD. The immune system is composed of immune cells and the proteins that these immune cells produce. Normally, these cells and proteins defend the body against harmful bacteria, viruses, fungi, and other foreign invaders. Activation of the immune system causes inflammation within the tissues where the activation occurs. (Inflammation is an important mechanism of defense used by the immune system.)

Normally, the immune system is activated only when the body is exposed to harmful invaders. In patients with IBD, however, the immune system is abnormally and chronically activated in the absence of any known invader. The continued abnormal activation of the immune system results in chronic inflammation and ulceration. The susceptibility to abnormal activation of the immune system is genetically inherited. Thus, first degree relatives (brothers, sisters, children, and parents) of patients with IBD are more likely to develop these diseases. Recently a gene called NOD2 has been identified as being associated with Crohn"s disease. This gene is important in determining how the body responds to some bacterial products. Individuals with mutations in this gene are more susceptible to developing Crohn"s disease.