Evaluation and Management of Diarrhea

Jenny S. Sauk

James M. Richter

Diarrhea is clinically characterized by the frequent passage of unformed stools. Episodes that are brief, self-limited, and well tolerated do not require medical attention, but when diarrhea becomes severe or chronic, a thoughtful evaluation is needed to ensure proper management. The primary care physician needs to know how to conduct an expeditious assessment of acute or severe diarrhea and coordinate a cost-effective approach to the evaluation of chronic diarrhea.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATIONS (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25)

Pathophysiology—Overview

The pathophysiologic common denominator is increased stool water content, which may be a consequence of increased fluid secretion, decreased absorption, or altered bowel motility. At times, several mechanisms are operative. Increased fluid secretion can result from inflammation, hormones, or enterotoxins. The resulting secretory diarrhea has a stool volume that remains in excess of 1 L/24 h despite fasting, a low stool osmolality, and a normal stool electrolyte concentration. Decreased reabsorption of fluid occurs with abnormalities of the bowel mucosa, loss of reabsorptive surface, or the presence of unabsorbable, osmotically active materials in the bowel lumen, such as lactose in patients with lactase deficiency. Patients with diarrhea resulting from decreased reabsorption typi cally respond to fasting with a decrease in stool volume to less than 250 mL/24 h, an increase in stool osmolality, and low stool concentrations of sodium and potassium. Increased bowel motility decreases the contact time with the bowel mucosa, limiting fluid reabsorption. It can ensue after vagotomy or may be chemically stimulated, as in hypergastrinemia or with the use of laxatives.

Acute Diarrheas

A diarrhea is categorized as “acute” if its duration is less than 2 weeks. Infectious causes dominate and include viral, bacte rial, and parasitic agents. Bacteria may cause diarrhea by pro ducing a toxin in contaminated food or after ingestion, or by invading the bowel mucosa. Some parasites invade the bowel wall, whereas others cling to it and alter the absorptive surface.

Viruses

Viruses causing acute gastroenteritis have long been the most common source of acute diarrhea in the United States, although it was not until the late 1970s that the responsible organisms were finally isolated and identified. Epidemics of viral gastroenteritis are particularly common. More than 70% of outbreaks of nonbacterial gastroenteritis investigated by the Centers for Disease Control and Prevention are linked to the noroviruses. In children, rotavirus infection is a common cause. Outbreaks have been found to occur during all seasons and involve waterborne, food-borne, and person-to-person modes of transmission. Rotavirus-induced diarrhea is uncommon among adults due to immunity from prior infection, but outbreaks have been documented (caused by the G2P[4] genotype) among the elderly living in large retirement communities.

Symptoms last about 1 week. The prominent symptom in children is vomiting, and in adults it is diarrhea. After an incubation period of 48 to 72 hours, symptoms usually begin abruptly with diarrhea, nausea, vomiting, headache, low-grade fever, abdominal cramps, and malaise; they resolve spontaneously within 24 to 96 hours. The diarrhea tends to be predominantly secretory in quality. Abdominal examination reveals diffuse tenderness (without guarding) and hyperactive bowel sounds. The white blood cell count is usually normal but may be elevated.

Staphylococcus aureus

Staphylococcus aureus is a common contaminant of custard-filled pastries and processed meats. The organism produces an enterotoxin that causes nausea, vomiting, abdominal cramps, and diarrhea within 2 to 8 hours after contaminated food has been eaten. Symptoms usually last less than 12 hours. A common-source pattern and lack of fever are typical.

Clostridium perfringens

Clostridium perfringens is another common food contaminant, especially of foods that have been warmed on steam tables. The organism releases an enterotoxin in the intestine. Consequently, the incubation period of 8 to 24 hours is a bit longer than that for staphylococcal food poisoning. It too has a common-source epidemiology; fever is absent. Symptoms include diarrhea, abdominal cramps, and occasionally some vomiting.

Bacillus cereus

Bacillus cereus produces a heat-stable enterotoxin, typically found in rice. One form of toxin-induced illness leads to vomiting but no diarrhea; severe abdominal cramping and diarrhea characterize another. The incubation period is 8 to 16 hours after the ingestion of contaminated food. The symptoms are self-limited.

Escherichia coli 0157:H7

Escherichia coli 0157:H7 is increasingly being recognized as responsible for much food-borne diarrhea. It accounts for up to 2.5% of all cases of acute diarrhea and up to one third of cases of bloody acute diarrhea. Transmission to humans is usually by the ingestion of contaminated meat (typically hamburger) that is undercooked, but can also occur by ingestion of unpasteurized juices, raw fruits and vegetables. Person-to-person transmission also occurs. Peak incidence is in the summer months. The organism does not directly invade the bowel wall, but the two Shiga-like toxins it produces cause mucosal edema, ulceration, and hemorrhage. The mean incubation period is 3 days (range, 1 to 9 days). Among individuals who become symptomatic, the clinical presentation ranges from mild, crampy, nonbloody diarrhea to life-threatening hemorrhagic colitis complicated by hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura. The typical presentation starts with crampy abdominal pain, followed within hours by watery diarrhea that progresses to bloody stools. Children, the elderly, and compromised hosts are at greatest risk.

Salmonella

Salmonella species cause diarrhea by invading the bowel wall. Achlorhydric patients who lack the antibacterial action of normal gastric acidity are at increased risk. The most common form of Salmonella infection is a self-limited diarrheal illness resulting from the ingestion of contaminated food (eggs and poultry are the major sources). Children are at greatest risk; late summer and fall are the times of peak incidence. Although most episodes of salmonellosis are mild, debilitated patients are at risk for serious bacteremia. In the typical outpatient case, symptoms begin 12 to 36 hours after ingestion and resolve within 5 days, although diarrhea may persist for up to 2 weeks. The initial presentation is rather nonspecific, with watery diarrhea, cramps, nausea, vomiting, and fever. In addition to colonization, an enterotoxin is released that stimulates the secretory diarrhea. In later stages, invasion spreads to the large bowel, and leukocytes may be noted in the stool. A distinguishing feature of salmonellosis is that the leukocytes are often mononuclear cells. In severe cases, dysentery can develop.

Typhoid fever, a rare but “must-not-miss” form of Salmonella disease, is caused by infection with Salmonella typhi. About 500 cases occur in the United States each year, mostly among young people. Infections are both waterborne and food-borne. Although diarrhea develops in only a small percentage of patients with typhoid fever, it does occur. The classic and most severe form is a “pea soup” diarrhea developing in the 3rd week of illness. Early symptoms suggestive of the condition are progressive fever, relative bradycardia, evanescent rash on the trunk (“rose spots”), splenomegaly, cough, headache, and right lower quadrant abdominal pain.

Shigella

Shigella infection produces an invasive diarrheal illness. Transmission is by the fecal-oral route, and stubborn reservoirs include day care centers, Native American reservations, urban ghettos, and rural villages in developing countries. Young children are at greatest risk and often the source of infection within a family. The illness proceeds in two stages. First, colonization takes place in the small bowel, resulting in a watery diarrhea and periumbilical pain, followed in a few days by invasion of the large bowel, associated with frequent small stools, tenesmus, and polymorphonuclear leukocytes on smear. In florid cases, the patient has fever, toxicity, bloody diarrhea, nausea, vomiting, and cramps. Most often, the disease is subtler and may be difficult to distinguish from other diarrheal illnesses accompanied by fever.

Campylobacter jejuni

Campylobacter jejuni infection is responsible for more cases of diarrhea in the United States than either Salmonella or Shigella. Infection derives most often from animal sources, such as poultry and household pets; fecal transmission between people also occurs. The incubation period is 2 to 7 days. Clinically, the illness resembles that caused by Salmonella or Shigella; however, symptoms may persist longer. Although the illness is usually self-limited and resolves within 1 week, the relapse rate is as high as 20%. In half of all cases, a Gram stain of the stool shows characteristic curved, gram-negative rods arranged in “seagullwing” fashion.

Yersinia enterocolitica

Yersinia enterocolitica also causes an illness that resembles salmonellosis. It is acquired by eating contaminated meat or dairy products. The incubation period is 12 hours to 3 days. An intense, regional lymphoid reaction may arise in the terminal ileum (the portal of entry for the organism) and result in a clinical picture of fever, right lower quadrant abdominal pain, and diarrhea that can simulate the onset of Crohn disease. In 10% to 40% of patients, fever, arthralgias, polyarthritis, or erythema nodosum develops. The illness is usually self-limited.

Vibrio parahaemolyticus and Non-Toxin-Producing Vibrio cholerae

Vibrio parahaemolyticus and non-toxin-producing V. cholerae are pathogenic species that have caused outbreaks of diarrheal disease among people eating raw seafood, particularly oysters and sushi-style red snapper and salmon. The incubation period is measured in hours to several days. The illness that ensues is usually mild and self-limited, although an occasional patient may present with fever, nausea, vomiting, and crampy diarrhea. Patients with significant liver disease can develop septicemia from V. parahaemolyticus and should avoid raw seafood.

Listeria monocytogenes

Listeria monocytogenes is another of the food-borne pathogens found in tainted processed meats and poultry products and also in unpasteurized milk products. Person-to-person transfer does not occur. About 2,000 cases per year occur in the United States. Deaths are common, with mortality rates of 20% to 30% reported. The elderly, the immunocompromised, and pregnant women are at greatest risk, but even immunocompetent persons can develop a febrile diarrhea. The onset of symptoms is typically 1 to 2 days after exposure. The initial symptoms resemble those of a viral gastroenteritis (fever, cramps, myalgias, diarrhea, headache). Days to weeks later, meningitis and bacteremia may ensue, especially in the immunocompromised host.

Vibrio cholerae

Vibrio cholerae causes the prototypical toxin-mediated secretory diarrheal disease that results from drinking water contaminated with the organism. Most outbreaks are pandemic in the Indian subcontinent, Southeast Asia, Africa, and the Middle East. Isolated outbreaks have been reported in Mediterranean countries. In the United States, rare individual cases sometimes occur along the Gulf Coast. The disease ranges in severity from a mild illness to fulminant, life-threatening diarrhea with copious production of gray, watery, mucoid (“rice water”) stool. In severe cases, fluid losses may exceed 1 L/h and are accompanied by vomiting, muscle cramps, and severe thirst. Dehydration,
serious volume depletion, and a metabolic acidosis may ensue. In mild cases, the patient reports painless, nonbloody diarrhea of abrupt onset.

Entamoeba histolytica

Entamoeba histolytica usually exists in a commensal relationship with its host, and most patients harboring the protozoan are asymptomatic carriers. Occasionally, this relationship breaks down, and the amoeba invades the colonic wall; an acute bloody diarrhea is the result. The clinical presentation ranges from mild to fulminant illness. Occasionally, the illness is mistaken for inflammatory bowel disease (see Chapter 73), and it may have a protracted course with exacerbations and remissions. Asymptomatic carriers such as returning tourists and immigrants are often the source of infection in developed countries. Because the organism does not have a soil phase, amebiasis is not restricted to warmer climates. Well-documented outbreaks have occurred in the United States and Europe, in addition to those that originate in developing countries.

Giardia lamblia

Giardia lamblia is a leading parasitic cause of diarrhea, especially overseas but also in the United States. Infection with the flagellated protozoan is particularly common where water supplies are contaminated by human sewage, but the organism is also endemic to such areas as the Rocky Mountains and St. Petersburg, Russia. The exact means by which Giardia causes diarrhea is unsettled, although heavy infestations can lead to malabsorption by coating large areas of the small bowel, particularly the lower duodenum and upper jejunum. The majority of patients with giardiasis are asymptomatic, but the organism is being recognized more frequently as an important cause of acute, intermittent, and chronic diarrheas in the United States. The ensuing loose stools may be watery or greasy; mucus is often present, but blood is rare. The patient may complain of epigastric or periumbilical discomfort. Mild steatorrhea and malabsorption occur with heavy parasite burdens.

Cryptosporidium, Microsporidia, and Other Protozoans

Cryptosporidium, microsporidia, and other protozoans are increasingly recognized causes of acute watery diarrhea (and sometimes of chronic disease). Point-source outbreaks occur in addition to sporadic cases. Transmission is by person-to-person contact through stool or by water or food contaminated with the spore or oocyst forms of the organism. Intestinal inflammation may develop. Children and immunocompromised adults are at the greatest risk for severe and prolonged illness. A profuse, watery diarrhea can develop, with stool volumes that may exceed 3 L daily. Although the illness is usually self-limited, it may persist in immunocompromised hosts. A mild illness develops in otherwise healthy, immunocompetent patients; they may become infected during occupational contact (e.g., with animal dung). For such patients, symptoms resolve spontaneously within 5 to 21 days.

Diarrhea in HIV-Infected Patients

Diarrhea in HIV-infected patients is a major problem, with a host of possible etiologies (see Chapter 13). In HIV-infected persons who engage in receptive anal intercourse, the presentation may be one of diarrhea, tenesmus, and rectal pain. In this setting, polymicrobial etiologies are not uncommon and may include Neisseria, Giardia, E. histolytica, Campylobacter, Chlamydia, Shigella, Salmonella, and protozoans.

Traveler’s Diarrheas

Patients traveling from industrialized to developing nations are at considerable risk for the development of diarrhea. Etiologic agents include E. coli, Salmonella, Shigella, E. histolytica, G. lamblia, S. typhi, and V. cholerae. Invasive E. coli strains can also cause a dysentery syndrome. Toxigenic E. coli are responsible for a large proportion of cases labeled as “traveler’s diarrhea” or “turista.” Poor food-handling practices and contaminated water transmit the agent. With enterotoxin production, a watery diarrhea ensues because the toxin promotes fluid secretion in the small bowel.

Brainerd Diarrhea

Brainerd diarrhea remains an unexplained, probably infectious, self-limited diarrheal disease that often occurs in point-source outbreaks.

Drug-Induced Diarrheas

Drugs are an important cause of both acute and chronic diarrheas (Table 64-1).

Acute Diarrhea.

Mechanisms of acute diarrhea include excessive fluid secretion (alcohol, phenolphthalein, and castor oil), reduction of fluid absorption (magnesium-containing antacids), and stimulation of bowel motility (caffeine-containing beverages and herbal teas). An osmotic diarrhea with crampy pain and watery stools may follow oral or parenteral use of broad-spectrum antibiotics, which disrupt the salvage of unabsorbed carbohydrate by killing normal colonic flora.

Persistent Diarrhea—Clostridium difficile Infection/Pseudomembranous Colitis.

The widespread use of broad-spectrum antibiotics has resulted in a marked increase in incidence of C. difficile infection and the emergence of hypervirulent strains (e.g., BI/NAP1/027). Diarrhea results from bacterial overgrowth and toxin production by the organism; pseudomembranous colitis may ensue. The antibiotics initially identified with the condition were ampicillin and clindamycin, but most broad-spectrum agents have been implicated. Immunocompromised patients, the elderly, and those with underlying bowel disease are most susceptible. Other risk factors include use of proton pump inhibitors, recent hospitalization, and ongoing chemotherapy. The NAP1 strain dominates symptomatic cases. Fever, abdominal pain, and profuse watery stools that can become bloody characterize pseudomembranous colitis. Symptoms range from mild to severe, usually starting after the initiation of a course of antibiotics, but onset can be delayed for as much as 4 to 8 weeks after the cessation of antibiotics and persist for months, mimicking inflammatory bowel disease. The sigmoidoscopic finding of nodular, inflammatory ulcers or yellow-white mucosal plaques is characteristic. Recurrence is very common.

Chronic and Recurrent Diarrheas

Although the number of etiologies is vast, consideration of a few exemplary conditions provides a good sense of the range and types of presentations. In addition, a number of the causes of acute diarrhea may account for chronic or recurrent disease.

Irritable Bowel Syndrome

Irritable bowel syndrome is the most common of the motility disorders responsible for chronic diarrhea or hyperdefecation (see Chapter 74). It can present as diarrhea alternating with constipation or as chronic, recurrent diarrhea. In addition to
diarrhea and constipation, patients may complain of distention, cramping, and mucus-laden stools. The condition waxes and wanes over many years. Neither fever nor blood is present. Any rectal bleeding that may occur is secondary to anal trauma resulting from straining and passage of hard stool.

TABLE 64-1 Differential Diagnosis of Diarrhea

Acute Diarrhea		Chronic or Recurrent Diarrhea
Viruses		Protozoa
Noroviruses and Rotaviruses			Giardia lamblia
Bacterial Toxins			Entamoeba histolytica
	Staphylococcus		Cryptosporidium
	Clostridium	Inflammation
Bacteria			Ulcerative colitis
	Salmonella		Crohn disease
	Shigella		Ischemic colitis
	Escherichia coli (including 0157:H7)		Pseudomembranous colitis
	Escherichia coli (including 0157:H7)		Collagenous colitis
	Campylobacter		Lymphocytic colitis
	Yersinia	Drugs
	Bacillus cereus		Laxatives
	Vibrio parahaemolyticus		Antibiotics
	Vibrio cholerae		Quinidine
	Listeria		Guanethidine; other antihypertensive agents
Protozoa
	Giardia lamblia		Caffeine
	Entamoeba histolytica		Digitalis
	Cryptosporidium	Functional
	Microsporidia		Irritable bowel syndrome
Drugs			Diverticulosis
	Laxatives	Tumors
	Antibiotics		Bowel carcinoma
	Caffeine		Villous adenoma
	Alcohol		Islet cell tumors
	Antacids		Carcinoid syndrome
Functional			Medullary carcinoma of thyroid
	Anxiety
	Acute presentations of chronic or recurrent diarrhea (see next column)	Malabsorption
			Sprue
			Intestinal lymphoma
			Whipple disease
			Pancreatic insufficiency
			Alpha-beta lipoproteinemia
		Postsurgical
			Postgastrectomy dumping syndrome
			Enteroenteric fistulas
			Blind loops
			Parasympathetic denervation
			Short-bowel syndrome
			Postcholecystectomy diarrhea
		Other
			Cirrhosis
			Diabetes mellitus
			Heavy metal intoxication
			Other neurogenic diarrheas
			Hyperthyroidism
			Addison disease
			Pellagra
			Scleroderma
			Amyloidosis

Inflammatory Bowel Diseases

Inflammatory bowel diseases are typical of the diarrheas that result from inflammatory destruction of the bowel wall (see Chapter 73). Abdominal pain, bloody stools, purulent discharge, and fever are seen in patients with active disease affecting the large bowel. Extraintestinal manifestations may involve the skin, joints, liver, and eyes. Microscopic examination of the stool may show red cells and leukocytes but no pathogens.

Diabetic Enteropathy

Diabetic enteropathy results from diabetes-induced autonomic neuropathy (see Chapter 102). When the small bowel is involved, the ensuing stasis allows bacterial overgrowth. The bacteria deconjugate bile acids, which may also lead to fat malabsorption. With involvement of the large bowel, the patient can experience distressing nocturnal diarrhea. Postural hypotension, impotence, and other symptoms and signs of autonomic insufficiency may accompany the diarrhea and suggest the diagnosis.

Dumping Syndrome

Dumping syndrome is another motility disorder and is seen most commonly in patients who have undergone vagotomy and gastroenterostomy. Patients complain of sweating, postural light-headedness, tachycardia, and diarrhea following meals. Concentrated carbohydrates are most likely to trigger symptoms. Lying down minimizes symptoms, as does the avoidance of concentrated sweets. The onset of the syndrome is soon after surgery, and symptoms usually subside within 12 months, although they may persist. Besides dysmotility, osmotic factors may contribute, but their precise role is unclear.

Villous Adenoma

Villous adenoma of the rectosigmoid causes a secretory, noninflammatory chronic diarrhea. Watery diarrhea, independent of food and fluid intake, is typical; severe potassium depletion can result. In some patients with this tumor, excessive secretion of mucus occurs, with the loss of sufficient protein to produce hypoalbuminemia and a protein-losing enteropathy syndrome.

Malabsorption of Fat or Carbohydrate

Malabsorption of fat or carbohydrate can lead to an osmotic diarrhea, as occurs in patients with pancreatic insufficiency, sprue, and short-bowel syndrome. Some of the osmotically active substances may also stimulate increased bowel secretion of fluids and electrolytes. Malabsorption of fat characteristically presents as steatorrhea (foul, bulky, greasy stools). Patients may note that the stools seem to be “sticky” and difficult to flush down the toilet. Steatorrheic stools “float,” not because of their fat content, but because of an increase in trapped gas. Associated symptoms are a function of the severity of the caloric and vitamin deficiencies that ensue and may include weight loss, ecchymoses, bone pain, glossitis, muscle tenderness, and peripheral neuropathy. Cramping lower abdominal pain typically precedes bowel movements.

Celiac Sprue and Gluten Sensitivity/Wheat Allergy.

Of the malabsorptive causes of chronic diarrhea, celiac sprue is the best recognized and defined. Prevalence estimates range from 0.3% to 1.0% and have increased with improved methods of diagnosis and heightened awareness of the condition. A genetically predisposed inappropriate T-cell response to ingested gluten causes immune-mediated damage to the small-bowel mucosa. Although classically described as a disease of children, sprue may have its onset in adulthood, with almost one fifth of cases beginning in the sixth decade. Onset may occur during pregnancy or in the postpartum period. Presenting symptoms can be subtle and nonspecific; they may include episodic or nocturnal diarrhea, flatulence, and weight loss along with iron deficiency. Steatorrhea may be absent if disease is limited to the proximal small bowel. Bloating, fatigue, headache, and vague abdominal discomfort are common and
may be mistaken for symptoms of irritable bowel syndrome. Iron deficiency anemia may be the only manifestation. Extraintestinal manifestations include neurologic problems (peripheral neuropathy, ataxia, psychiatric disturbances), fractures (from vitamin D deficiency), and infertility. Characteristic serologic findings include antiendomysial and antitissue transglutaminase IgA antibodies. Defining histologic changes include villous atrophy, lymphocytic infiltrate, and crypt elongation.

Gluten sensitivity and wheat allergy are poorly defined conditions that may present in similar fashion to celiac disease, in that there is diarrhea and abdominal discomfort on exposure to gluten-containing foods. However, neither is associated with the characteristic autoantibodies or small-bowel histology of celiac disease. Rash and urticaria may help differentiate wheat allergy from related conditions, but symptoms are otherwise similar, though usually more rapid in onset (minutes to hours). Symptoms associated with gluten sensitivity are nearly identical to those of adult celiac disease.

Lactase Deficiency (Milk Intolerance)

Lactase deficiency (milk intolerance) leads to the malabsorption of lactose and an osmotic diarrhea. It is particularly common among African Americans, Native Americans, Asians, and Jews. Onset is typically in adulthood. A secondary form of the disease may develop in patients with extensive disease of the small bowel. Patients report nausea, bloating, cramps, and diarrhea after ingesting more than their customary intake of milk products. Weight loss and steatorrhea are absent or mild; appetite remains good. Avoidance of milk products (except for yogurt containing live cultures, which provide lactase) terminates symptoms. Diagnosis may be confirmed by a trial of abstinence and by abnormal results on hydrogen breath testing (which detects excessive hydrogen production resulting from the bacterial metabolism of undigested lactose).

Laxative Abuse

Laxative abuse is an important etiology of chronic diarrhea. Patients with eating disorders (see Chapter 234) tend to use laxatives constantly and surreptitiously in a relentless attempt to lose weight. Depending on the type of agent used, either a secretory or an osmotic diarrhea may develop. Agents associated with secretory diarrheas include castor oil and phenolphthalein preparations. Osmotic diarrheas occur when the patient takes a preparation that contains magnesium (e.g., milk of magnesia) or another poorly absorbable substance. These substances appear in the stool and can be tested for if laxative abuse is suspected. Patients who abuse laxatives may present with unexplained dehydration, electrolyte depletion, or preoccupation with weight loss.

Lymphocytic Colitis and Collagenous Colitis (“Microscopic Colitis”)

These two recently described conditions associated with chronic watery diarrhea occur predominantly in older women. The colonic appearance is grossly normal, but biopsy reveals collagenous or lymphocytic infiltrates. Celiac disease, thyroid disease, and irritable bowel syndrome are more prevalent in patients with microscopic colitis than the general population.

Bile Acid Diarrhea

Bile acid diarrhea is seen after cholecystectomy and ileal resection. It is an irritant diarrhea caused by the action of excessive bile acids on the bowel and responds to bile acid sequestrants (e.g., cholestyramine).

Incontinence

A number of patients who complain of “diarrhea” actually suffer from incontinence. Typically, their stool volumes are normal (<2.5 mL/d), although their stools may be soft; poor sphincter tone and evidence of stool incontinence are found on physical examination (see Chapter 66).