ATHEROSCLEROSIS

Arteriosclerosis .. is a general term for several diseases where the arterial walls
become thick and lose elasticity independently of cause this thickening. There are
five main form of arteriosclerosis:
1. atherosclerosis (the most common).
2. Mönckeberg’s arteriosclerosis (calcification of small arteries, usually in
the elderly, also called medial calcific sclerosis).
3. Inflammatory arteriosclerosis (syphilitic).
4. Hyperplastic arteriolosclerosis is associated with malignant hypertension
or necrotizing vasculitis and is characterized by "onionskin hyperplasia,"
i.e., concentric thickening of the intima, deposition of basophilic ground
substance, smooth muscle proliferation, and hypertrophy of the
adventitia.
5. Hyaline arteriolosclerosis is associated with diabetes, hypertension, and
old age. Arteriolar sclerosis (arteriolosclerosis, mostly caused by
hypertension in arterioles particularly in the kidney, spleen and
pancreas).It is characterized by hyaline thickening of arterioles that
narrows the vessel lumen.

Atheroscleros
is
is a type of arteriosclerosis. It comes from the Greek words athero (meaning gruel or paste)
and sclerosis (hardness).
Atherosclerosis is a chronic disease affecting primarily the intima of large and medium-
sized arteries and is characterized by fibrolipid plaques or atheromas. Atherosclerosis is the
commonest arterial diseases.
Epidemiology. It is known that the most common cause of death (40%) is cardiovascular
diseases, most of witch are related to atherosclerosis. Epidemiologic investigations on
living populations have revealed a number of risk factors, which are associated with
increased risk of developing clinical atherosclerosis.
The risk factors are often acting in combination rather than singly.
The first of them is age. Early atherosclerotic lesions may be present in childhood, but
clinical manifestations will appear later. In scientific research, which have been performed at
our department, morphological signs of atherosclerosis were found in the fetus and new-
born aorta.
The second of risk factors is sex. The incidence and severity of atherosclerosis are higher in
men than in women.
Genetic factors play a significant role in atherosclerosis. There is familial predisposition to
atherosclerosis which may be related to other risk factors like diabetes, hypertension and
hyperlipoproteinemia.
Geographic factors also play a role. There is a high incidence of atherosclerosis in the
Europe, Australia, and US.

Hyperlipidemia.
Elevated serum cholesterol levels, especially low density
lipoprotein (LDL) and very low-density lipoprotein (VLDL).
Many studies have demonstrated specific effects of diet
including the amount of dietary cholesterol ingested on
lipid and lipoprotein levels.
Hypertension is a major risk factor in atherosclerosis
development. It acts probably by mechanical injury to the
arterial wall due to increased blood pressure.
Other factors are diabetes mellitus, smoking, obesity, etc.

Pathogenesis
There are several pathogenesis theories of atherosclerosis: Virchow's, Rokitansky's, Anychkow's,
Benditt's. Historically, two hypotheses for atherogenesis were dominant: one emphasized cellular
proliferation in the intima as a reaction to insudation of plasma proteins and lipids from the blood,
whereas the other postulated that organization and repetitive growth of thrombi resulted in plaque
formation. The contemporary view of the pathogenesis of atherosclerosis incorporates elements of
both older theories and is called the response to injury hypothesis. Formulated in 1973 and modified in
1986 and 1993, it states that atherosclerotic lesions are initiated as a response to some form of injury to
arterial endothelium. The injury is a form of endothelia dysfunction without necessary denudation,
which increases permeability to plasma constituents, including lipids, and permits blood monocytes
and eventually platelets to adhere to endothelium. Monocytes adhere and subsequently enter the intima,
transform into macrophages, and accumulate lipid to become foam cells, contributing, to the evolution
of the lesion. Factors released from, activated platelets at the surface or monocytes then cause migration
of smooth muscle cells from media into the intima followed by proliferation and synthesis of
extracellular matrix components by smooth muscle.cells, leading to the accumulation of collagen and
proteoglycans. Single or short-lived injurious events can be followed by restoration of endothelial
function and regression of the lesion. Repeated or chronic injury, however, results in the development
of an atheromatous plaque, probably by permitting continuing increased permeability, ingress of
monocytes, or perhaps platelet interactions.
One of the more recent theories suggests that excess lipoproteins, LDL, in the blood are trapped within
the artery wall. When this happens and they accumulate, they become oxidized. That leads to
"modified" lipoproteins which are rapidly taken up by smooth muscle cells. This, in turn, leads to the
formation of foam cells that lead to the deposition of connective tissue cells and elements.
Dislipoproteinemia – disturbance of ratio between low density lipoprotein (LDL), very low-density
lipoprotein (VLDL) and high density lipoprotein (HDH) it is one of the main causes of atherosclerosis.

Morphology
. Although the fibrous and
complicated plaques are the
atherosclerotic lesions
associated with disturbances in
blood front that cause clinical
disease states, the morphologic
changes of diffuse intimal
thickening and fatty streaks may
be either precursors of the basic
atherosclerotic lesion or stages
in its development

1.Intimal thickening. Fibromuscular thickening of the intima of arteries may be a part of atherosclerotic
process, particularly rapid during the first two decades of life. Macroscopically, the lesions may appear as small
white areas of intimal cushion at the bifurcation and branching of arteries, or many be appear as «diffuse
intimal thickening». Microscopically, the lesions consist of smooth muscle cells, fibrous tissue, some collagen
but no lipid.
2.Fatty streaks especially prominent in the aorta and major arteries, more often on the posterior wall than
the anterior wall. Macroscopically, the lesions may appear as flat or slightly elevated and yellow. They may be
either in the form of small (about l mm in size) or in the form of elongated, beaded streaks. Microscopically,
fatty streaks lying under the endothelium are composed of closely-packed foam cells, lipidcontaining
elongated smooth muscle cells and a few lymphoid cells. Small amount of extracellular lipid, collagen and
proteoglycans are also present. The cholesterol esters in foam cells of fatty streaks differ chemically from
those in the lipid core of atheromatous fibrous plague. These dissimilarities might be explained on the basis of
two types of fatty streaks, which differ in morphology, cellular genotype, and lipid content, with one type
related to the fibrous plague and the other type not related
3. Fibrous plaque (atheroma). The lesions are raised, pearly white to grey, smooth-surfaced, plaque
like structures in the intima but may extend into the media, may encroach considerably on the vascular
lumen, especially in muscular arteries such as coronary arteries. On cross section a typical lesion has a soft,
yellow central zone with gruel-like material covered on the luminal aspect by a layer of dense fibromuscular
tissue (fibrous cap).
In general, plaques are found most often in the abdominal aorta, large arteries of the lower limbs, carotid
arteries, proximal portions of the coronary arteries and circle of Willis.
The histologic appearance of lesions varies considerably depending on the relative amounts of the different
components. The central atheroma of an uncomplicated fibrous plague consist of acellular, amorphous,
electron-dense material that contains lipids, cellular debris, fibrin and other plasma proteins. The fibrous cap is
composed of avascular connective tissues and elongated smooth muscle cells covered by endothelium.
Inflammatory cells, including macro-phages, may be present. In older and more advanced lesions the collagen
in the fibrous cap may be dense and hyalinised, smooth muscle cells may be atrophic and foam cells are fewer.

4. Complicated plaques develop from preexisting fibrous plaques as a result of one of a
combination of several pathologic changes that include calcification, ulceration, thrombosis and
haemorrhage. The complicated lesion is the most common type of atherosclerotic lesion that
produces significant circulatory change and clinical disease.
A..Calcification the intima is brittle and cracks like an eggshell when the vessel is opened. Micro
scopically the dystrophic calcific process involves both the fibrous cap and the atheromatous
portion of the plaque.
B..Ulceration and thrombosis. Advanced fibrous plaques with soft pultaceous atheromas, especially
those with calcification may ulcerate as a result of mechanical or hemodynamic forces. With
ulceration, cholesterol or lipid debris from the atheroma may be discharged and embolize. Mural
thrombi may form on the ulcer or at sites of endothelial damage or mural hemorrhage. Such
thrombi also may become organized and incorporated within the intimal plaque. Mural thrombi in
medium-sized arteries may progress to occlusive thrombi that may reconalize.
C..Hemorrhage into atherosclerotic plaque is a common finding in advanced lesions, especially in
the coronary arteries. The blood may reach the lesion from the vascular lumen through surface
ulcerations or from rapture of capillaries that vascularized the atheroma from adventitial vasa
vasoram.
D..With secondary changes in the media:
1) the internal elastic lamina is attenuated and fragmented.
2) smooth muscle cells and elastic lamina atrophy is connected a form of aneurysmal dilatation,
which may follow, especially in elastic arteries.

Microscopically
following states of atherosclerosis are distinguished:
1. prelipidosis,
2. lipidosis,
3. liposclerosis,
4. atheromatosis,
5. ulceration,
6. atherocalcification.

There are several clinico-
morphological types of atherosclerosis
according to localization. There are:
1) Atherosclerosis of aorta;
2) Atherosclerosis of coronary arteries;
3) Atherosclerosis of cerebral artery;
4) Atherosclerosis of arteries of lower
extremities;
5) Atherosclerosis of arteries of small
intestine;
6) Atherosclerosis of renal arteries.

The clinical effects result from
the following:
 Slow luminal narrowing causing ischemia
and atrophy.
 Suddenly luminal occlusion causing
infarction necrosis.
 Propagation of plaque by formation of
thrombi and emboli.
 Formation of aneurysmal dilation and
eventual rapture.

The symptomatic atherosclerotic disease involves most often
the heart, brain, kidneys, small intestine and lower extremities.
Some of the important effects are listed below: Aorta aneurysm
formation, thrombosis and embolization to other organs; Heart -
myocardial infarction, ischemic heart disease; Brain - chronic
ischemic brain damage (senile dementia), cerebral infarction;
Small intestine - ischemic bowel disease, infarction; Lower
extremities - intermittent claudication, gangrene. Kidney -
chronic ischemic renal damage, sclerosis, atrophy.
Aorta aneurysm is a wall bulge out. Aneurysms may be true
and false. True aneurysms: all 3 tunics of the wall bulge out
together
False - Blood contained by a clot.
Depend on the shape aneurysms may be fusiform, saccular.
A dissecting aneurysm occurs when the layers of the artery
separate from each other. Dissecting saccular aneurysm - blood
is contained by the adventitia. This is a possible sequela of
atherosclerosis. <6 cm rarely ruptures; 80% of larger ones
rupture. Mortality: 5% pre-rupture 50% post-rupture.
Most of them may be as a cause of death.

ISCHAEMIC HEART DISEASE
(CORONARY ARTERY DISEASE)
Ischemic heart disease is caused by an imbalance between the myocardial blood
flow and the metabolic demand of the myocardium.
The World Health Organization’s Study group on Atherosclerosis and Ischemic
Heart Disease defined ischemic heart disease (IHD) as the cardiac disability,
acute and chronic, arising from reduction or arrest of blood supply to the
myocardium in association with disease processes in the coronary arterial
system. Synonymous: coronary heart disease (CHD), atherosclerotic heart
disease (ASHD), coronary artery disease (CAD).
The American Heart Association has classified risk factors developing IHD:
Major risk factors cannot be changed: Heredity. Sex (gender).Race. Age.
Major risk factors that can b changed: Cigarette smoking. Hypertension.
Hypercholesterolemia. Diabetes mellitus. Contributing factors Obesity. Lack of
physical exercise. Emotional stress
Depending upon the suddenness of onset, duration, degree, location and extent
of the area affected by myocardial ischemia, there can be 2 types of ischemic
manifestation: acute and chronic.

Acute:
1.Myocardial infarction.
2.Non-infarct effects of myocardial ischemia; which.include the following:
A.angina pectoris;
B.sudden cardiac death.
Chronic:
1.Chronic atherosclerotic heart disease (atherosclerotic cardiosclerosis).
2.Postinfarction myocardiosclerosis.
3.Chronic aneurism of the heart.

Myocardial infarction is the most significant in the human pathology.
In industrialized countries myocardial infarction accounts for 10-25 % of all deaths.
About 5 % of heart attacks occur in young people under the age of 40 years, especially
with hypertension, diabetes mellitus, cigarette smoking and etc.
Myocardial infarction is an ischemic myocardial cell necrosis.
Etiology: causes of MI include coronary artery obstruction due to the progressive
development of atherosclerosis; coronary artery spasm; embolism, thrombosis.
Myocardial infarction has been classified in a number of ways by the physicians and the
pathologists:
1.According to the anatomic region of the left ventricle involved. They are called anterior,
posterior, lateral, septal and circumferential.
2.According to the degree of thickness of the ventricular wall involved:
full-thickness or transmural, when they involve the entire thickness of the ventricular
wall; subendocardial or lamina, when they occupy the inner subendocardial half of the
myocardium, intramural, subepicardial.
3. According to the age of infarcts:
A)newly-formed infarcts are called acute, recent or fresh;
B)advanced infarcts are called old, healed or organized.

Infarctions are most frequently located in the left ventricle. Beside it may be located in other parts
of the heart. But it is observed rarely. The region of infarction depends upon the area of obstructed
blood supply by one or more of the three coronary arterial trunks.
1.Stenosis of the left anterior descending coronary artery is the most common (40-50%).
2.Stenosis of the right coronary artery is the next most frequent (30-40%).
3. Stenosis of the left circumflex coronary artery is seen least frequently (15-20%).
Pathologic changes. The macroscopic and microscopic changes in the myocardial infarction
according to the age of the infarct. On gross examination, an acute myocardial infarct is not
identifiable within the first 12 hours after the onset. By 24 hours, the infarct can be recognized on
the cut surface of the involved ventricle by its pallor. After 3 to 5 days, the infarct is mottled and
more sharply outlined, with a central pale, yellowish, necrotic region bordered by a hyperemic zone.
By 2 to 3 weeks infracted region is depressed and soft, with a refractile, gelatinous appearance.
Older, healed infarcts are firm and contracted and have the pale gray appearance of scar tissue.
Microscopically the majority of infarcts occur singly and vary in size from 4 to 10 cm. During the
first week the colour of infarct charges from cyanotic red to bright yellow or yellow-green. The
consistency of infarct in this period is soft.
During the second week infarct has red periphery and during the fourth to sixth week it is a thin,
grey-white, hard, shrunken fibrous scar.
Microscopically during the first week we may see coagulative necrosis and marginal neutrofilic
infiltration, then beginning of resorption of necrosed fibres by macrophages, onset of fibrovascular
response; neutrofilic infiltration disappear. During the fourth to sixth week-increased fibrocollagenic
tissue, decreased blood supply, fewer pigmented macrophages, lymphocytes and plasma cells.
Using special methods such as electron microscopy, chemical and histochemical studies, the
changes can be demonstrated in early infarcts before detectable light microscopic alterations
appear.

Complications
 About 10% patients with acute myocardial infarction develop cardiogenic shock,
which is characterized by hypertension with systolic blood pressure of 80 mm Hg
or less for many days.
 Shock may be accompanied by peripheral circulatory failure, oliguria and mental
confusion. A lot of patients with myocardial infarction suffer from congestive heart
failure, which may be in the form of right ventricular, left ventricular failure or
both. This complication is responsible for about 40% of deaths from acute
myocardial infarction.
 Arrhythmias are the most common form of complication in acute myocardial
infarction.
 Mural thrombosis and thromboembolism from intracardiac thrombi and from
thrombosis in the leg veins is observed 15-45% in cases of acute myocardial
infarction.
 Usually in the first week heart rapture may develop. It is often fatal.
 Cardiac aneurysm often develops in the left ventricle; it impairs the function of the
heart and is a site for mural thrombi.
 Fibrinous pericarditis appears on about the second day of myocardial infarction. As
a rale, this complication develops in the patients with transmural myocardial
infarction.
 About 3-4% of patients who suffered from acute myocardial infarction develop
post-myocardial infarction syndrome. It is characterized by pneumonitis. The main
causes of death are complications of myocardial infarction.

Non-infarct effects of myocardial ischemia
1.Angina pectoris is clinical syndrome of Coronary artery disease. Dystrophy and
necrobiosis are revealed in the myocardial cells due to which transient myocardial
pain in the substernal or pericardial region of the chest occurs.
2.Chronic Coronary artery disease (Myocardial fibrosis). Myocardial fibrosis may be
focal or diffuse. Development mechanism of myocardial fibrosis can be different.
Macroscopically the left ventricular wall generally shows the fact of grey-white
fibrosis in brown myocardium. Microscopically there are areas of diffuse myocardial
fibrosis, especially around the small blood vessels in the interstitial tissue of the
myocardium.
3.Sudden cardiac death is defined as sudden death within 24 hours of the onset of
cardiac symptoms. In the majority of cases it is caused by Coronary artery disease,
coronary vasospasm, calcific aortic stenosis, myocarditis, hypertrophic
cardiomyopathy, hereditary and acquired defects of the conduction system.
The autopsy in such cases reveals most commonly critical atherosclerotic coronary
narrowing.

HYPERTANSIVE VASCULAR DISEASE
In medically advanced countries, hypertension is the most common serious chronic
disease, affecting about half the population over 50 years of age.
Essential, primary, or idiopathic hypertension is defined as high blood pressure in
which secondary causes such as renovascular disease, renal failure, pheochromocytoma,
aldosteronism, or other causes of secondary hypertension or mendelian forms
(monogenic) are not present. Essential hypertension accounts for 95% of all cases of
hypertension.
The World Health Organization has defined hypertension as a systolic pressure
greater than 160 mm Hg or a diastolic pressure greater than 90 mm Hg, or both.
Hypertensive heart disease or hypertensive cardiomyopathy is the disease of the heart
resulting from systemic hypertension of prolonged duration and manifesting by left
ventricular hypertrophy. Often hypertension predisposes to atherosclerosis.
The arterial changes and vascular complications increase with the severity and duration
of the hypertension, but are modified by genetic factors, environmental factors, sex
(females tolerate hypertension better), and associated diseases.
The increased peripheral resistance resulting in sustained hypertension may arise from:
1)increased sympathetic tone;
2) increased release of renin and generation of angiotensin (2);
3)the presence of vasoconstrictive substances in the circulation;
4)increased sodium load and extracellular fluid load and finally
5)a postulated excessive responsiveness to the other factors.
In a given individual hypertension may be attributable to a combination of these
factors.

Hypertension is classified into two types
1.Primary or essential hypertension in which the cause of increase in blood pressure in
unknown. This hypertension constitutes about 90—95% patients of hypertension.
2.Secondary hypertension, in which the increase in blood pressure is caused by diseases of
the kidneys, endocrine or some other organs. This hypertension comprises 5-10% causes of
disease.
According to the clinical course, both types of hypertension may be benign or malignant.
Benign hypertension is moderate elevation of blood pressure and the rise is slow as the
years pass. About 90% patients of hypertension have benign disease.
Malignant hypertension is marked and rapid increase of blood pressure to 200/140 mm Hg or
more and the patients have papilledema, hemorrhages and hypertensive encephalopathy.

Primary (essential) hypertension
The cause of this hypertension is unknown. But there are a lot of factors are related to its
development. There are as under:
1)genetic factors - the evidences in support are the familial aggregation;
2)racial and environmental factors - surveys in the US have revealed higher incidence of
primary hypertension in blacks than in whites.
A number of environmental factors have been implicated in the development of this type of
hypertension including salt intake, obesity, skilled occupation, higher living standards and
patients in high stress.
There are some factors modifying the course of essential hypertension:
A)age - younger the age at which hypertension is first noted but left untreated, B)lower the life
expectancy;
C)sex - females tolerate hypertension better than males;
atherosclerosis - as a rule, accompanies essential hypertension.
The pathogenetic mechanism are:
1) high plasma level of catecholamines;
2) increase in blood volume, i.e. arterial overfilling (volume hypertension) and arteriolar
constriction (vasoconstrictor hypertension);
3) increased cardiac output;

Morphology.
The morphological effects of systemic
hypertension are manifested as lesions in the
heart, peripheral vessels, kidneys and brain.
Accordingly it we distinguish several clinical and
morphological types of essential hypertension.
There are:
1) cardio-vascular,
2) renal,
3) cerebral.

Hypertensive heart disease is an important and common form of heart disease
in all world. Macroscopically, the most significant finding is marked hypertrophy
of the heart, especially of the left ventricle. The weight of the heart increases to
500- 700 gm (may be 1000 gr) (normal weight is about 300 gr). The weight of
the heart is directly related to the severity of hypertension but there is no
correlation between the weight of the heart and duration of hypertension. The
left ventricular wall is thickened (up to 20 mm or more), the papillary muscles
are rounded and prominent, and the cardiac chamber is small (concentric
hypertrophy). However, when decompensation and cardiac failure develop,
there is eccentric hypertrophy with thinning of the ventricular wall and dilation of
the left ventricular and atrial cavities. There may be dilation and hypertrophy of
right heart as well.
Changes in the blood vessels involve arterioles and arteries. There are 3types
of these changes:
1.hyaline arteriolosclerosis that results in homogeneous and eosinophilic
thickening of the wall of small blood vessels,
2.intimal thickening due to proliferation of smooth muscle cells in the intima –
elastofibrosis in middle vessels – splitting of elastic membrane due to
overgrowth of fibrous tissue.
3.In the large blood vessels atherosclerosis usually develops.

Renal type of hypertension may be benign and malignant. Benign
nephrosclerosis is the term used to describe the kidney of benign
phase of hypertension. Macroscopically, both kidneys are affected
equally and are reduced in size and weight, often weighing about 100
gm or less. The capsule is often adherent to the cortical surface. The
surface of the kidney is finely granular and shows V-shaped areas of
scarring («small contracted kidney»primarily). The cut surface shows
firm kidney and narrowed cortex. Microscopically there arc primarily
diffuse vascular changes, which produce parenchymal changes
secondarily as a result of ischaemia, parenchymal changes. There is
variable degree of atrophy of parenchyma. These include glomerular
shrinkage, deposition of collagen in Bowman's space,
periglomerular fibrosis. Clinical features is variable: elevation of the
blood pressure with headache, dizziness, palpitation. Renal failure
and uremia may occur.

1. Cerebrovascular diseases (cerebral type).
Hypertension can result in two main types of parenchymal diseases of the brain:
1)ischemic brain damage (hypoxic encephalopathy and cerebral infarction);
2)intracranial hemorrhage (intracerebral and subarachnoid hemorrhage).
The pathologic appearance of the brain in hypoxic encephalopathy varies depending on the duration and
severity of hypoxic episode and the length of survival. Macroscopically, there is focal softening. The area
supplied by distal branches of the cerebral arteries suffers from the most severe ischemic damage and may
develop border zone or watershed infarcts in the adjacent zones between the territories supplied by major
arteries. Microscopically, the nerve cells die and disappear and are replaced by reactive fibrillary glia.
Cerebral infarction is a localized area of tissue necrosis caused by local vascular occlusion. Clinically, the signs
and symptoms associated with cerebral infarction depend on the region infracted. Cerebral infarcts may be
anemic or hemorrhagic.
Macroscopically, an anemic infarct becomes evident 6-12 hours after its occurrence. The affected area is soft
and swollen and there is blurry of junction between grey and white matter. Within 2--3 days, the infarct
undergoes softening and disintegration, A hemorrhagic infarct is red and superficially resembles a hematoma. It
is usually the result of fragmentation of occlusive arterial emboli or venous thrombosis. Hemorrhage into the
brain of patient with hypertension, is intracerebral hemorrhage, which is usually of hypertensive origin.
Most hypertensives over middle age have microaneurism in very small cerebral arteries in the brain tissue. The
common sites of hypertensive intracerebral hemorrhage are the region of the basal ganglia, pons and
cerebella's cortex. About 40% of patients die during the first 3-4 days of hemorrhage, mostly from hemorrhage
into the ventricles. The outcome of intracerebral hemorrhage is cyst formation.

The causes of death among hypertensive patients
were the following:
 congestive heart failure;
 coronary artery disease;
 cerebrovascular accidents;
 uremia;
 causes unrelated to hypertension. The
cardiac complications therefore account
for 36% of the death.

Secondary hypertension
may be classified as follows:
1. Renal:
A) vascular diseases (coarctation (narrowing) of the aorta, atherosclerosis, arteritis, mechanical
obstruction attributable to thrombosis, embolism, tumors);
B) parenchymal renal diseases (glomerulo- nephritis, pyelonephritis, hydronephrosis, amyloidosis,
tumors);
c) perinephric diseases (perinephritis, tumors, hematoma).
2. Cerebral:
a) increased intracranial pressure (trauma, inflammation, tumors);
B)anxiety states;
lesions of brainstem (poliomyelitis).
3.Cardiovascular: coarctation of aorta (aorta has narrow).
4.Endocrine:
A) pheochromocytoma;
B) adrenocortical adenomas;
pituitary adenomas;
C) hyperthyroidlsm.
5.Preeclampsia and eclampsia.
If these causes of secondary hypertension are eliminated, hypertension disease can cured.