6 Homeostasis Flashcards

You may prefer our related Brainscape-certified flashcards:
1
Q

homeostasis

A

involves physiological control systems that maintain the internal environment within restricted limits.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

The importance of maintaining a stable core temperature and stable blood pH in relation to enzyme activity.

A

enzymes that control the biochemical reactions within cells, and other proteins, such as channel proteins, are sensitive to changes in pH and temp
any change to these factors reduces the rate of reaction of enzymes or may even prevent them working altogether
maintaining a fairly constant internal environment means that reactions take place at a suitable rate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

The importance of maintaining a stable blood glucose concentration in terms of availability of respiratory substrate and of the water potential of blood.

A

changes in water potential of the blood and tissue fluids may cause cells to shrink and expand as a result of water leaving or entering by osmosis
in both instances the cells cannot operate normally
the maintenance of a constant blood glucose conc is essential in ensuring a constant water potential
a constant blood glucose conc also ensures a reliable source of glucose for respiration by cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

advantages of organisms with the ability to maintain a constant internal environment

A

they are more independent of changes in the external environment
may have a wider geographical range and therefore have a greater chance of finding food, shelter etc.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

control mechanisms

A

the control of any self-regulating system involves a series of stages that feature:

  • the optimum point
  • receptor
  • coordinator
  • effector
  • feedback mechanism
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

the optimum point - control mechanism

A

the point at which the system operates best

monitored by a receptor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

receptor- control mechanism

A

detects any deviation from the optimum point (ie a stimulus) and informs the coordinator

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

coordinator- control mechanism

A

coordinates the info from receptors and sends instructions to an appropriate effector

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

effector- control mechanism

A

often a muscle or gland, which brings about the changes needed to return the system to the optimum point
this return to normality creates a feedback mechanism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

feedback mechanism - control mechanism

A

by which a receptor responds to stimulus created by the change to the system brought about by the effector

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

positive feedback

A

occurs when a deviation from an optimum causes changes that result in an even greater deviation from the normal
e.g. in neurones where a stimulus leads to a small influx of sodium ions. this influx increases the permeability of the neurone membrane to sodium ions, more ions enter, causing a further inc in permeability and even more rapid entry of ions. in this way, a small stimulus can bring about a large and rapid response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

ectotherms

A

animals that obtain a proportion of their heat from sources outside their bodies, namely their environment

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

endotherms

A

animals that derive most of their heat from the metabolic activities that take place inside their bodies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

regulation of body temp in ectotherms

A

eg lizards

  • expose themselves to sun: orient themselves so max SA of their body exposed to sun rays
  • taking shelter
  • gaining warmth from ground
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

regulation of body temp in endotherms- cold environment

A

physiological mechanisms

  • vasoconstriction
  • shivering
  • raising of hair
  • inc metabolic rate
  • decrease in sweating
  • behavioural mechanisms
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

regulation of body temp in endotherms- warm environment

A

physiological mechanisms

  • vasodilation
  • inc sweating
  • lowering body hair
  • behavioural mechanisms
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

vasoconstriction

A

diameter of arterioles near surface of skin is made smaller
reduces volume of blood reaching skin surface through the capillaries
most of the blood entering the skin passes beneath the insulating layer of fat and so loses little heat to environment

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

vasodilation

A

diameter of arterioles near surface of skin becomes larger
allows warm blood to pass close to skin surface through the capillaries
the heat from this blood is then radiated away from the body

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

negative feedback

A

occurs when the stimulus causes the corrective measures to be turned off
in doing so this tends to return the system to its original level
there are separate negative feedback mechanisms to regulate departures from the norm in each direction

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

fall in conc of blood glucose summary

A

stimulus is detected by receptors on the surface of alpha cells (coordinator) in the pancreas
these alpha cells secrete the hormone glucagon
glucagon causes the liver cells (effectors) to convert glycogen to glucose which is released into the blood, raising the blood glucose conc
as this blood with raised blood glucose concs circulates back to the pancreas there is a reduced stimulation of alpha cells which then secrete less glucagon
negative feedback- the secretion of glucagon leads to a reduction in its own secretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

rise in conc of blood glucose summary

A

insulin would be produced form the beta cells in the pancreas
insulin increases the uptake of glucose by cells and its conversion into glycogen and fat
the fall in blood glucose conc that results reduces insulin production once blood glucose concs return to their optimum
negative feedback

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

hormones

A

differ from one another chemically but all have certain characteristics in common:

  • produced in glands, which secrete hormones directly into the blood (endocrine glands)
  • carried into the blood plasma to the cells on which they act- known as target cells- which have specific receptors on their cell-surface membranes that are complementary to a specific hormone
  • are effective in very low concs, but often have widespread and long-lasting effects
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

second messenger model

A

a mechanism of hormone action

this mechanism is used by two hormones involved in the regulation of blood glucose conc, namely adrenaline and glucagon

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

mechanism involving adrenaline- second messenger model

A
  • adrenaline binds to a transmembrane protein receptor within the cell-surface membrane of a liver cell
  • the binding of adrenaline causes the protein to change shape on the inside of the membrane
  • this change of protein shape leads to the activation of an enzyme called adenyl cyclase. the activated adenyl cyclase converts ATP to cyclic AMP (cAMP)
  • the cAMP acts as a second messenger that binds to protein kinase enzyme, changing its shape and therefore activating it
  • the active protein kinase enzyme catalyses the conversion of glycogen to glucose which moves out of the liver cell by facilitated diffusion and into the blood, through channel proteins
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

role of pancreas in regulating blood glucose

A

produces enzymes for digestion and hormones (insulin and glucagon) for regulating blood glucose conc
made up largely of the cells that produce its digestive enzymes. scattered throughout these cells are groups of hormone-producing cells known as islets or Langerhans

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

islets of Langerhans

A

groups of hormone producing cells
the cells of islets of Langerhans include:
-alpha cells, which are larger and produce the hormone glucagon
-beta cells, which are smaller and produce the hormone insulin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

role of the liver in regulating blood sugar

A

glycogenesis
glycogenolysis
gluconeogenesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

pancreas

A

large, pale-coloured gland

situated in the upper abdomen, behind the stomach

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

liver

A

located immediately below the diaphragm

made up of cells called hepatocytes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

glycogenesis

A

the conversion of glucose into glycogen

when blood glucose conc is higher than normal the liver removes glucose from the blood and converts it to glycogen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

glycogenolysis

A

the breakdown of glycogen to glucose
when the blood glucose conc is lower than normal, the liver can convert stored glycogen back into glucose which diffuses into the blood to restore the normal blood glucose conc

32
Q

gluconeogenesis

A

the production of glucose from sources other than carbohydrate
when its supply of glycogen is exhausted, the liver can produce glucose from non-carbohydrate sources such as glycerol and amino acids

33
Q

regulation of blood glucose conc

A

if conc of glucose falls too low, cells will be deprived of energy and die
if the conc rises too high, it lowers the water potential of the blood and creates osmotic problems that can cause dehydration and be equally dangerous

34
Q

factors that influence blood glucose conc

A

blood glucose comes from three sources:

  • directly from the diet in the form of glucose absorbed following hydrolysis of other carbohydrates such as starch, maltose, lactose and sucrose
  • from the hydrolysis in the small intestine of glycogen=glycogenolysis stores in the liver and muscle cells
  • from gluconeogenesis, which is the production of glucose from sources other than carbohydrate
35
Q

insulin and the beta cells of the pancreas

A

the beta cells of the islets of Langerhans in the pancreas have receptors that detect stimulus of a rise in blood glucose conc and respond by secreting the hormone insulin directly into the blood plasma
almost all body cells (not rbc) have glycoprotein receptors on their cell surface membranes that bind specifically with insulin molecules

36
Q

what happens when insulin combines with receptors

A

insulin brings about:

  • a change in the tertiary structure of the glucose transport carrier proteins, causing them to change shape and open, allowing more glucose into the cells by facilitated diffusion
  • an inc in the number of carrier proteins responsible for glucose transport in the cell-surface membrane. at low insulin conc, the protein from which these channels are made is part of the membrane of vesicles. a rise in insulin conc results in these vesicles fusing with the cell-surface membrane so increasing the number of glucose transport channels
  • activation of the enzymes that convert glucose to glycogen and fat
37
Q

in what ways is the blood glucose conc lowered

A
  • by inc the rate of absorption of glucose into the cells, especially in muscle cells
  • by inc the respiratory rate of cells, which therefore use up more glucose, thus increasing their uptake of glucose from the blood
  • by inc the rate of conversion of glucose into glycogen (glycogenesis) in the cells of the liver and muscles
  • by inc the rate of conversion of glucose to fat
38
Q

glucagon and the alpha cells of the pancreas

A

the a cells of the islets of Langerhans detect a fall in blood glucose conc and respond by secreting the hormone glucagon directly into the blood plasma
glucagon’s actions include:
-attaching to specific protein receptors on the cell-surface membrane of liver cells
-activating enzymes that convert glycogen to glucose
-activating enzymes involved in the conversion of amino acids and glycerol into glucose (=gluconeogenesis)

39
Q

role of adrenaline in regulating the blood glucose level

A

there are at least four other hormones apart from glucagon that can inc blood glucose conc
best known is adrenaline
at times of excitement or stress, adrenaline is produced by the adrenal glands that lie above the kidneys. adrenaline raises the blood glucose conc by:
-attaching to protein receptors on the cell surface membranes of target cells
-activating enzymes that causes the breakdown of glycogen to glucose in the liver

40
Q

hormone interaction in regulating blood glucose

A

the two hormones insulin and glucagon act in opposite directions insulin lowers the blood glucose conc, where as glucagon increases it.
the two hormones are said to act antagonistically
the system is self regulating through negative feedback in that it is the conc of glucose in the blood that determines the quantity of insulin and glucagon produced
in this way the interaction of these two hormones allows highly sensitive control of the blood glucose conc
the conc of glucose is not, however, constant, but fluctuates around an optimum point
this is because of the way neg feedback mechanisms work
only when the bg conc falls below the set point is insulin secretion reduced, leading to a rise in bg conc
in the same way, only when the conc exceeds the set point is glucagon secretion reduced, causing a fall in the blood glucose conc

41
Q

diabetes

A

a metabolic disorder caused by an inability to control blood glucose conc due to a lack of the hormone insulin or a loss of responsiveness to insulin

42
Q

type one diabetes

A

insulin dependent
due to the body being unable to produce insulin
normally begins in childhood
may be the result of an autoimmune response whereby the body’s immune system attacks its own cells, in this case the beta cells of the islets of Langerhans
type one develops quickly, usually over a few weeks

43
Q

type two diabetes

A

insulin independent
normally due to glycoprotein receptors on body cells being lost or losing their responsiveness to insulin
may also be due to an inadequate supply of insulin from the pancreas
type two usually develops in people over the age of 40 years
there is, however, an increasing number of cases of obesity and poor diet leading to type two diabetes in adolescents
it develops slowly
people who are overweight are particularly likely to develop it
about 90% of ppl with diabetes have type 2

44
Q

signs of diabetes

A
high blood glucose conc
presence of glucose in urine
need to urinate excessively
genital itching or regular episodes of thrush
weight loss
blurred vision
45
Q

symptoms of diabetes

A

tiredness

blurred vision

46
Q

control of type one diabetes

A

controlled by injections of insulin
cannot be taken orally as is a protein so would be digested
injected typically either two or four times a day
dose of insulin must be matched exactly to the glucose intake
if a person takes too much insulin, they will experience a low blood glucose conc that can result in unconsciousness
to ensure the correct dose, blood glucose conc is monitored using biosensors
by injecting insulin and managing their carbohydrate intake and exercise carefully, people can lead normal lives

47
Q

control of type 2 diabetes

A

usually controlled by regulating the intake of carbohydrate in the diet and matching this to the amount of exercise taken
in some cases, this may be supplemented by injections of insulin or by the use of drugs that stimulate insulin production
other drugs can slow down the rate at which the body absorbs glucose from the intestine

48
Q

osmoregulation

A

the homeostatic control of the water potential of the blood

49
Q

structure of mammalian kidney

A

fibrous capsule- outer membrane that protects the kidney
cortex- a light coloured outer region made up of renal (Bowman’s) capsules, convoluted tubules and blood vessels
medulla-darker coloured inner region made up of loops of Henle, collecting ducts and blood vessels
renal pelvis- funnel shaped cavity that collects urine into the ureter
ureter- tube that carries urine to bladder
renal artery- supplies kidney w blood from heart via the aorta
renal vein- returns blood to the heart via the vena cava

50
Q

nephron

A

the functional unit of the kidney

a narrow tube up to 14mm long, closed at one end, with two twisted regions separated by a long hairpin loop

51
Q

structure of nephron

A
renal (bowman's) capsule
proximal convoluted tubule
loop of henle
distal convoluted tube
collecting duct
52
Q

renal (bowman’s) capsule

A

the closed end at the start of the nephron
it is cup-shaped and surrounds a mass of blood capillaries known as the glomerulus
the inner layer of the renal capsule is made up of specialised cells called podocytes

53
Q

proximal convoluted tubule

A

a series of loops surrounded by blood capillaries

its walls are made of epithelial cells which have microvilli

54
Q

loop of henle

A

a long, hairpin loop that extends from the cortex into the medulla of the kidney and back again
it is surrounded by blood capillaries

55
Q

distal convoluted tubule

A

a series of loops surrounded by blood capillaries

its walls are made of epithelial cells, but it is surrounded by fewer capillaries than the proximal tubule

56
Q

collecting duct

A

a tube into which a number of distal convoluted tubules from a number of nephrons empty
it is lined by epithelial cells and becomes increasingly wide as it empties into the pelvis of the kidney

57
Q

what blood cells are associated with the nephron?

A

afferent arteriole
glomerulus
efferent arteriole
blood capillaries

58
Q

afferent arteriole

A

a tiny vessel that ultimately arises from the renal artery and supplies the nephron with blood
the afferent arteriole enters the renal capsule of the nephron where it forms the glomerulus

59
Q

glomerulus

A

a many branched knot of capillaries from which fluid is forced out of the blood
the glomerular capillaries recombine to form the efferent arteriole

60
Q

efferent arteriole

A

a tiny vessel that leaves the renal capsule
it has a smaller diameter than the afferent arteriole and so cases an inc in blood pressure within the glomerulus
the efferent arteriole carries blood away from the renal capsule and later branches to form the blood capillaries

61
Q

blood capillaries

A

a concentrated network of capillaries that surrounds the proximal convoluted tubule, the loop of henle and the distal convoluted tubule and from where they reabsorb mineral salts, glucose and water
these capillaries merge together into venules (tiny veins) that in turn merge tog to form the renal vein

62
Q

role of the nephron

A

osmoregulation
carries this out in a series of stages:
-the formation of glomerular filtrate by ultrafiltration
-reabsorption of glucose and water by the proximal convoluted tube
-maintenance of a gradient of sodium ions in the medulla by the loop of Henle
-reabsorption of water by the distal convoluted tubule and collecting ducts

63
Q

formation of glomerular filtrate by ultrafiltration

A

blood enters kidney through renal artery, branches into many tiny arterioles, each entering a renal (Bowman’s) capsule of a nephron
this afferent artery divides to give a complex of capillaries known as the glomerulus which later merge to the efferent arteriole, which then subdivides again into capillaries
as the diameter of the afferent arteriole is greater than that of the efferent arteriole, there is a build up of hydrostatic pressure within the glomerulus
resulting in water, glucose and mineral ions being squeezed out of the capillary to form the glomerular filtrate
blood cells and proteins cannot pass across into the renal capsule as they are too large

64
Q

what resists the movement of glomerular filtrate out of the glomerulus?

A
  • capillary epithelial cells
  • connective tissue and epithelial cells of the blood capillary
  • epithelial cells of the renal capsule
  • the hydrostatic pressure of the fluid in the renal capsule space
  • the low water potential of the blood in the glomerulus
65
Q

what reduces the resistance to allow the flow of glomerular filtrate?

A
  • the inner layer of the renal capsule is made up of highly specialised cells called podocytes. these cells have spaces between them. this allows filtrate to pass beneath them and through gaps between their branches. filtrate passes between these cells either than through them
  • the endothelium of the glomerular capillaries has spaces up to 100nm wide between its cells. fluid can therefore pass between rather than through these cells
66
Q

reabsorption of glucose and water by the proximal convoluted tubule

A

in the PCT nearly 85% of the filtrate is reabsorbed back into the blood

  • sodium ions are actively transported out of the cells lining the proximal convoluted tubule into the blood capillaries which carry them away. the sodium ion conc of these cells is therefore lowered.
  • sodium ions now diffuse down a conc gradient from the lumen of the PCT into the epithelial lining cells but only through special carrier proteins by facilitated diffusion
  • these carrier proteins are of specific types, each of which carries another molecule (glucose or AAs etc) along with the sodium ions. co transport
  • the molecules which have been co transported into the cells of the PCT then diffuse into the blood. as a result, all the glucose and most other valuable molecules are reabsorbed as well as water
67
Q

how is the PCT adapted to reabsorb substances into the blood?

A

by having epithelial cells which have:

  • microvilli to provide a large SA to reabsorb substances from the filtrate
  • infoldings at their bases to give a large SA to transfer reabsorbed substances into blood capillaries
  • a high density of mitochondria to provide ATP for active transport
68
Q

maintenance of a gradient of sodium ions by the loop of Henle

A
  • sodium ions are actively transported out of the ascending limb of the loop of Henle using ATP provided by the many mitochondria in the cell of its walls
  • this creates a low water potential in the region of the medulla between the two limbs (the interstitial region). the thick walls are almost impermeable to water so very little if any escapes
  • the walls of the descending limb are very permeable to water and so it passes out of the filtrate by osmosis into the interstitial space. this water enters the blood capillaries in this region by osmosis and is carried away
  • the filtrate progressively loses water in this way as it moves down the descending limb lowering its water potential. it reaches its lowest wp at the tip of the hairpin
  • at the base of the ascending limb, sodium ions diffuse out of the filtrate and as it moves up the ascending limb these ions are also actively pumped out and therefore the filtrate develops a progressively higher water potential
  • in the interstitial space between the ascending limb and the collecting duct there is a gradient of water pot with the highest water pot in the cortex and an inc lower water pot the further into the medulla one goes
  • the collecting duct is permeable to water and so as the filtrate moves down it, water passes out of ir by osmosis. this water passes by osmosis into the blood vessels that occupy this space, and is carried away
  • as water passes out of the filtrate its water pot is lowered. however the water pot is also lowered in the interstitial space and so water continues to move out by osmosis down the whole length of the collecting duct. the counter-current multiplier ensures that there is always a water pot gradient drawing water out of the tubule
69
Q

two regions of the loop of Henle

A
  • the descending limb which is narrow with thin walls that are highly permeable to water
  • the ascending limb which is wider with thick walls that are impermeable to water
70
Q

the distal convoluted tubule

A

the cells that make up the walls of the dct have microvilli and many mitochondria that allow them to reabsorb material rapidly from the filtrate by active transport
the main role of the distal tubule is to make final adjustments to the water and salts that are reabsorbed and to control the pH of the blood by selecting which ions to reabsorb
to achieve this, the permeability of its walls becomes altered under the influence of various hormones

71
Q

counter-current multiplier

A

the filtrate in the collecting duct with a lower water pot meets interstitial fluid that has an even lower water pot
meaning that although the water pot gradient is small, it exists for the whole length of the collecting duct
there is therefore a steady flow of water into the interstitial fluid, so that around 80% of the water enters the interstitial fluid and hence the blood

72
Q

regulation of the water potential in the blood- fall in water pot

A
  • cells called osmoreceptors in the hypothalamus of the brain detect a fall in water pot
  • when water pot of blood is low water is lost from osmoreceptor cells by osmosis
  • due to this water loss the osmoreceptor cells shrink, a change that causes the hypothalamus to produce antidiuretic hormone ADH
  • ADH passes in to the posterior pituitary gland from where it is secreted into the capillaries
  • ADH passes in the blood to the kidney, where it increases the permeability to water of the cell-surface membrane of the cells that make up the walls of the distal convoluted tubule and the collecting duct.
  • specific protein receptors on the cell surface membrane of these cells bind to ADH molecules, leading to activation of an enzyme called phosphorylase within the cell
  • the activation of phosphorylase causes vesicles within the cell to move to, and fuse with, its cell surface membrane
  • these vesicles contain pieces of plasma membrane that have numerous water channel proteins (aquaporins) and so when they fuse with the membrane the number of water channels is considerably increased, making the cell surface membrane more permeable to water
  • ADH increases the permeability of the collecting duct to urea, which therefore passes out, further lowering the water pot of the fluid around the duct
  • the combined effect is that more water leaves the collecting duct by osmosis, down a water pot gradient, and re enters the blood
  • as the reabsorbed water came from the blood in the first place, this will not, in itself, inc the water pot of the blood, but merely prevent it getting lower. the osmoreceptors also send nerve impulses to the thirst centre of the brain.
  • the osmoreceptors in the hypothalamus detect the rise in water pot and send fewer impulses to the pituitary gland
  • the pituitary gland reduces the release of ADH and the permeability of the collecting ducts to water and urea reverts to its former state. negative feedback
73
Q

regulation of the water potential in the blood- rise in water pot

A
  • the osmoreceptors in the hypothalamus detect a rise in water pot and inc the freq of nerve impulses to the pituitary gland to reduce its release of ADH
  • less ADH, via the blood, lead to a decrease in the permeability of the collecting ducts to water and urea
  • less water is reabsorbed into the blood from the collecting duct
  • more dilute urine is produced and the water pot of the blood falls
  • when the water pot of the blood has returned to normal, the osmoreceptors in the hypothalamus cause the pituitary to raise ADH release back to normal levels neg feedback)
74
Q

detection and secretion- blood glucose levels

A

blood glucose conc detected by alpha or beta cells in the pancreas
glucagon or insulin is secreted and travels in the blood to the liver cells
the hormones bind to the receptors on the liver cell membranes to initiate glycogenesis, glycogenolysis or gluconeogenesis

75
Q

what are primary messangers

A

are messengers that do not enter a cell.
Primary messengers exert an action on the cell membrane by binding to receptors and triggering a change within the cell.
This change can be the activation of another molecule (a secondary messenger) or it may initiate a reaction. Hormones are examples of primary messengers (e.g. adrenaline and glucagon).

76
Q

what are secondary messangers

A

Secondary messengers initiate and coordinate responses that take place inside a cell.
Secondary messengers are usually activated by the binding of a primary messenger to a cell surface receptor.
Cyclic AMP (cAMP) is an example of a secondary messenger.