Heating device and polypeptide synthesis equipment

Abstract

The embodiment of the utility model provides a heating device and polypeptide synthesis equipment. The heating device comprises a supporting plate; the heating piece is arranged on the supporting plate, a placing hole and a heating circulation channel surrounding the placing hole are formed in the heating piece, and the placing hole is used for inserting a piece to be heated; and the connecting piece is arranged on the supporting plate and located below the placing hole, and the connecting piece is used for being detachably connected with the to-be-heated piece inserted into the placing hole. The liquid in the heating circulation channel can exchange heat with the to-be-heated piece through the heating piece, so that the to-be-heated piece can be heated. Due to the fact that the heating circulation channel surrounds the containing hole, the to-be-heated piece can be heated from the periphery, and the heating speed is high. Moreover, as the liquid in the heating circulation channel flows, the liquid with reduced temperature after heat exchange can flow out, and the liquid with high temperature can flow in, the heating circulation channel can keep the to-be-heated part at a constant temperature.

Description

TECHNICAL FIELD

[0001] The utility model relates to polypeptide synthesis technical field, specifically, it relates to a heating device and polypeptide synthesis equipment with it. BACKGROUND

[0002] As a key field of biological medicine innovation and research and development, polypeptide synthesis technology has broad development prospects. With its high biological activity, high specificity, low side effects and difficulty in accumulation in the body, polypeptide drugs have become a global hot spot for new drug research and development. At present, more than 80 polypeptide drugs have been approved for listing in the world, and the market size reached 62.8 billion US dollars in 2020, and is expected to grow to 96 billion US dollars in 2025, showing strong growth momentum.

[0003] The traditional scheme needs to put the resin into the reaction cup. The resin can be used as a solid carrier, which is usually pre-activated and has a protective group such as Fmoc (fluorenylmethyloxycarbonyl). Then, a 20% piperidine solution can be added to the reaction cup, so that the resin can be deprotected, and then the Fmoc protective group at the N-terminal can be removed. Then, a gas such as nitrogen can be added to the reaction cup, so that bubbling (condensation reaction) can be carried out. Then, subsequent processes can be carried out, and finally all amino acids are connected to the resin in a predetermined order to form a complete polypeptide chain.

[0004] However, the temperature of the reaction cup of the above scheme is uncontrollable, which causes the resin and the piperidine solution to be unable to fully contact, and the reaction speed cannot be effectively controlled. Therefore, the efficiency of polypeptide synthesis is low. UTILITY MODEL CONTENT

[0005] In order to at least partially solve the problems existing in the prior art, according to one aspect of the utility model, a heating device is provided. The heating device comprises: a support plate; a heating piece, the heating piece is arranged on the support plate, the heating piece is provided with a placing hole and a heating circulation channel surrounding the placing hole, the placing hole is used for inserting a to-be-heated piece; and a connecting piece, the connecting piece is arranged on the support plate and located below the placing hole, and the connecting piece is used for detachably connecting with the to-be-heated piece inserted into the placing hole.

[0006] Exemplarily, the front side of the heating piece is provided with an observation hole, and the observation hole is in communication with the placing hole.

[0007] Exemplarily, the observation hole is located below the heating circulation channel.

[0008] Exemplarily, a plurality of placing holes are arranged on the heating piece in intervals, the connecting piece is correspondingly located below the plurality of placing holes, and the heating circulation channel surrounds the plurality of placing holes.

[0009] Exemplarily, the connecting piece is provided with a liquid inlet and an air inlet which are in communication with the to-be-heated piece.

[0010] Exemplarily, the liquid inlet and the gas inlet are completely staggered along the extension direction of the connecting piece.

[0011] Exemplarily, the heating device further comprises a bubbling assembly arranged on one side of the heating piece and below the connecting piece, the bubbling assembly being configured to bubble gas into the to-be-heated piece through the gas inlet.

[0012] Exemplarily, the bubbling assembly comprises a gas source three-way piece, a stop valve and a speed regulating valve, which are sequentially connected with the gas inlet along the flow direction of the gas.

[0013] Exemplarily, a plurality of placing holes are arranged on the heating piece at intervals, the connecting piece is correspondingly arranged below the placing holes, and the bubbling assembly further comprises a flow dividing piece, the flow dividing piece being provided with a gas inlet hole and a plurality of gas outlet holes, the gas inlet hole penetrating through the flow dividing piece, one end of the stop valve being connected to the gas source three-way piece and the other end being connected to two ends of the gas inlet hole, one end of each of the plurality of gas outlet holes being communicated to the middle part between the two ends of the gas inlet hole, and the speed regulating valve being correspondingly connected between the other end of each of the plurality of gas outlet holes and the gas inlet.

[0014] According to another aspect of the present application, a polypeptide synthesis device is also provided. The polypeptide synthesis device comprises any one of the heating devices described above.

[0015] The heating device provided by the present application can heat the to-be-heated piece when the to-be-heated piece is inserted into the placing hole and connected to the connecting piece. The liquid in the heating circulation channel can exchange heat with the to-be-heated piece, so that the to-be-heated piece can be heated. Since the heating circulation channel surrounds the placing hole, the to-be-heated piece can be heated from all directions, and the heating rate is high. Moreover, since the liquid in the heating circulation channel flows, the liquid with a reduced temperature after heat exchange can flow out, and the liquid with a high temperature can flow in, so that the heating circulation channel can keep the to-be-heated piece at a constant temperature. The to-be-heated piece can be used for reactions such as resin deprotection, and the to-be-heated piece can be heated to keep the temperature of the to-be-heated piece within the optimal temperature threshold required by the reaction, so that the reactants can be fully contacted, thereby improving the speed and effect of the reaction.

[0016] A series of simplified forms are introduced in the content of the present application, which will be further described in detail in the specific embodiment part. The content part of the present application does not mean to try to limit the key features and necessary technical features of the claimed technical solution, and does not mean to try to determine the protection scope of the claimed technical solution.

[0017] The advantages and features of the present application will be described in detail below with reference to the drawings. BRIEF DESCRIPTION OF DRAWINGS

[0018] The following drawings for the utility model are hereby incorporated as part of the utility model for the purpose of understanding the utility model. The drawings show the embodiments of the utility model and the description thereof, which are used to explain the principles of the utility model. In the drawings,

[0019] Figure 1 is a perspective view of a heating device according to an exemplary embodiment of the utility model;

[0020] Figure 2 is Figure 1 is a sectional view of the heating element shown in Fig. 2 along the extension direction of the heating circulation channel;

[0021] Figure 3 is Figure 1 is a sectional view of the heating element shown in Fig. 2 along the extension direction of the placement hole; and

[0022] Figure 4 is Figure 1 is a bottom view of the heating element shown in Fig. 2, wherein the heating circulation channel is schematically shown by a dashed line.

[0023] Among them, the above drawings include the following reference signs:

[0024] 100, heating device; 200, support plate; 300, heating element; 310, placement hole; 320, heating circulation channel; 321, inlet; 322, outlet; 323, first heating hole; 324, second heating hole; 325, third heating hole; 326, fourth heating hole; 330, observation hole; 340, sensor hole; 400, connecting piece; 420, air inlet; 500, bubbling assembly; 510, speed regulating valve; 520, flow dividing piece; 521, air inlet hole; 522, air outlet hole; 531, tee; 532, air inlet pipe; 533, air outlet pipe; 600, to-be-heated element. DETAILED DESCRIPTION

[0025] In the following description, a large number of details are provided so as to enable a thorough understanding of the utility model. However, it can be appreciated by those skilled in the art that the following description only exemplarily shows the preferred embodiments of the utility model, and the utility model can be implemented without one or more such details. In addition, in order to avoid confusion with the utility model, some technical features known in the art are not described in detail.

[0026] According to an aspect of the utility model, a heating device is provided. The heating device can heat a to-be-heated element. The heating device can be applied to any suitable equipment, including but not limited to a polypeptide synthesis equipment. Therefore, according to another aspect of the utility model, a polypeptide synthesis equipment is also provided. The heating device and the polypeptide synthesis equipment of the embodiments of the utility model will be described in detail below with reference to the drawings.

[0027] As Figures 1-4 shown, the heating device 100 can include a support plate 200, a heating member 300, and a connecting member 400.

[0028] The support plate 200 can serve as a base of the heating device 100 to fix the heating member 300 and the connecting member 400.

[0029] The heating member 300 can be disposed on the support plate 200 by any suitable means such as welding, adhesion, or screwing, and thus can be fixed to the support plate 200. The heating member 300 can be provided with a placement hole 310 and a heating circulation passage 320. The placement hole 310 can be used for insertion of a to-be-heated member 600. The to-be-heated member 600 includes but is not limited to a reaction cup or a test tube. The heating circulation passage 320 can surround the placement hole 310. The heating circulation passage 320 can have an inlet 321 and an outlet 322. A liquid such as hot water or hot oil can enter the heating circulation passage 320 through the inlet 321, flow around the placement hole 310, and then flow out through the outlet 322. The inlet 321 can be used for connection to a heat source for supplying the liquid. The outlet 322 can be used for connection to a tank for recovering the liquid. Exemplarily, the inlet 321 and the outlet 322 can be located at the rear side of the heating member 300 to leave more space for the front side. The orientation term "rear" used herein and hereinafter generally refers to the side away from the relevant person. Therefore, the orientation term "front" used hereinafter generally refers to the side close to the relevant person. That is, the relevant person can generally perform relevant work at the front side of the heating member 300. Exemplarily, the heating circulation passage 320 can generally have a rectangular, circular, or spiral shape along the extension direction thereof, as long as it can surround the placement hole 310. In some embodiments, the heating circulation passage 320 can include a first heating hole 323, a second heating hole 324, a third heating hole 325, and a fourth heating hole 326 provided on the heating member 300. The first heating hole 323 and the second heating hole 324 can respectively extend in the front-rear direction and be located at the left and right sides of the heating member 300. The third heating hole 325 and the fourth heating hole 326 can respectively extend in the left-right direction and be located at the front and rear sides of the heating member 300. The end of the first heating hole 323 can be configured as the inlet 321. The end of the second heating hole 324 can be configured as the outlet 322. The ends of the third heating hole 325 and the fourth heating hole 326 can be respectively plugged with sealing plugs. The third heating hole 325 and the fourth heating hole 326 can respectively communicate with the first heating hole 323 and the second heating hole 324 at the left and right sides of the heating member 300. The first heating hole 323, the second heating hole 324, the third heating hole 325, and the fourth heating hole 326 can surround the placement hole 310. In this way, the liquid entering the first heating hole 323 through the inlet 321 can flow to the third heating hole 325 and the fourth heating hole 326, respectively, and then converge in the second heating hole 324 before flowing out through the outlet 322. Exemplarily, the first heating hole 323, the second heating hole 324, the third heating hole 325, and the fourth heating hole 326 can be located at the same horizontal plane. The hole diameters of the first heating hole 323, the second heating hole 324, the third heating hole 325, and the fourth heating hole 326 can be the same.

[0030] The connecting piece 400 can be arranged on the support plate 200 by any suitable manner such as welding, adhesion or screw connection. The connecting piece 400 can be located below the placing hole 310. The connecting piece 400 can be used to detachably connect with the to-be-heated piece 600 inserted into the placing hole 310. The detachable connection structure includes but is not limited to a snap connection structure, a screw connection structure or an interference fit plug-in structure.

[0031] The heating device 100 provided by the embodiment of the present application can heat the to-be-heated piece 600 by heat exchange between the heating piece 300 and the to-be-heated piece 600 when the to-be-heated piece 600 is inserted into the placing hole 310 and connected to the connecting piece 400. The to-be-heated piece 600 can be heated because the heating circulation channel 320 surrounds the placing hole 310 and can heat the to-be-heated piece 600 from all directions. The heating rate is high. The liquid in the heating circulation channel 320 flows, the liquid with a reduced temperature after heat exchange can flow out, and the liquid with a high temperature can flow in, so that the heating circulation channel 320 can keep the to-be-heated piece 600 at a constant temperature. The to-be-heated piece 600 can be used to perform a reaction such as resin deprotection. The to-be-heated piece 600 can be heated to keep the temperature of the to-be-heated piece 600 within the optimal temperature threshold required by the reaction, so that the reactants can be fully contacted, thereby improving the speed and effect of the reaction.

[0032] The inlet 321 of the heating circulation channel 320 can be connected to a thermostat (not shown) for example. The thermostat can start a water heating cycle. When the water temperature reaches the set temperature, hot water can flow out of the thermostat, flow back to the inside of the thermostat after passing through the heating circulation channel 320, and be heated again, thereby completing a constant temperature cycle.

[0033] The heating piece 300 can be made of any suitable material such as plastic, copper or iron. The heating piece 300 can be made of aluminum for example. Aluminum is a metal with good thermal conductivity, and its thermal conductivity coefficient is about 237 W / m·K (Watt per meter per Kelvin), which makes it very ideal as a heat conduction material. In addition, aluminum is light in weight and low in cost, and its high reflectivity also helps to improve its efficiency in heat exchange.

[0034] The heating piece 300 can also be provided with a sensor hole 340 for example. The sensor hole 340 can be connected to the heating circulation channel 320. The heating device 100 can also include a sensor connected to the sensor hole 340. The sensor can be used to detect the temperature of the liquid in the heating circulation channel 320, so as to cooperate with the controller and the above-mentioned thermostat and other components to achieve the purpose of accurately controlling the temperature of the liquid.

[0035] Exemplarily, the front side of the heating member 300 can be provided with an observation hole 330. The observation hole 330 can be in communication with the placement hole 310. The observation hole 330 can be circular, rectangular or any other suitable shape. In the embodiment shown in the figure, the observation hole 330 can be a waist hole extending along the extension direction of the placement hole 310. The line of sight of the relevant personnel can pass through the observation hole 330, so that the state (for example, the reaction progress and / or the reaction speed) of the to-be-heated member 600 in the placement hole 310 can be observed.

[0036] Exemplarily, the observation hole 330 can be located below the heating circulation channel 320. Since the reactants are usually deposited at the bottom of the to-be-heated member 600, by arranging the observation hole 330 below the heating circulation channel 320, the relevant personnel can observe the state of the to-be-heated member 600 at the bottom. Moreover, since the observation hole 330 can cause the structural strength of the heating member 300 to decrease, by arranging the observation hole 330 close to the support plate 200, the support plate 200 can inhibit the influence of the observation hole 330 on the structural strength of the heating member 300.

[0037] Exemplarily, a plurality of placement holes 310, for example, two, three or more, can be arranged on the heating member 300. In the embodiment shown in the figure, the number of placement holes 310 can be ten. The plurality of placement holes 310 can be arranged in a straight line, an arc or any other suitable manner. The structure of each placement hole 310 can be the same or different. The connecting member 400 can be located below each of the plurality of placement holes 310 one by one. The heating circulation channel 320 can surround the plurality of placement holes 310. Each of the plurality of placement holes 310 can be used to insert a to-be-heated member 600, each to-be-heated member 600 can work independently, and the working efficiency of the heating device 100 is high. Moreover, the heating circulation channel 320 can heat the plurality of placement holes 310 at the same time, and the structure is simple and convenient for processing and manufacturing.

[0038] Exemplarily, the connecting member 400 can be provided with a liquid inlet (not shown due to angle) and an air inlet 420. When the to-be-heated member 600 is inserted into the placement hole 310 and connected to the connecting member 400, the liquid inlet and the air inlet 420 can be in communication with the to-be-heated member 600, respectively. For example, a liquid such as a piperidine solution can enter the to-be-heated member 600 through the liquid inlet. For example, a gas such as nitrogen can enter the to-be-heated member 600 through the air inlet 420. In this way, the connecting member 400 not only can be used to fix the to-be-heated member 600, but also can provide a connection structure for the to-be-heated member 600 to provide liquid and air.

[0039] Exemplarily, the liquid inlet and the air inlet 420 can be arranged on the side wall of the connecting member 400. The liquid inlet can be arranged on the rear side of the connecting member 400. The air inlet 420 can be arranged on the front side of the connecting member 400.

[0040] Exemplarily, the liquid inlet and the gas inlet 420 can be completely staggered along the extension direction of the connecting piece 400. In this way, the liquid entering the connecting piece 400 through the liquid inlet will not directly impact on the gas inlet 420, so as not to be discharged through the gas inlet 420. Similarly, the gas entering the connecting piece 400 through the gas inlet 420 will not directly impact on the liquid inlet, so as not to be discharged through the liquid inlet.

[0041] Exemplarily, the heating device 100 can further comprise a bubbling assembly 500. The bubbling assembly 500 can be arranged at one side of the heating piece 300. Moreover, the bubbling assembly 500 can be located below the connecting piece 400. The bubbling assembly 500 can be used to bubble the gas into the to-be-heated piece 600 through the gas inlet 420. In this way, the heating device 100 has more functions, so as to be applicable to more work.

[0042] Exemplarily, the bubbling assembly 500 can comprise a gas source triple joint (not shown), a stop valve (not shown) and a speed regulating valve 510. Along the flow direction of the gas, the gas source triple joint, the stop valve, the speed regulating valve 510 and the gas inlet 420 can be connected in sequence. The gas source triple joint can be used to connect to a gas source. Therefore, the bubbling assembly 500 can further comprise a gas source. The gas source can supply the gas, which can pass through the gas source triple joint, the stop valve, the speed regulating valve 510 and the gas inlet 420 in sequence, so as to enter the to-be-heated piece 600. The gas source triple joint can purify, filter and reduce the pressure of the passing gas to the expected pressure. The stop valve can be used to control the on-off of the gas. The speed regulating valve 510 can be used to adjust the flow of the gas, so as to control the reaction speed in the to-be-heated piece 600 by controlling the gas inlet amount in the to-be-heated piece 600. The speed regulating valve 510 comprises but is not limited to an electromagnetic speed regulating valve or a manual speed regulating valve. Exemplarily, the speed regulating valve 510 can comprise a manual speed regulating valve, which has a relatively simple structure and a relatively low cost. The manual speed regulating valve can be located at the front side of the heating piece 300, so as to facilitate the operation of the relevant personnel.

[0043] Exemplarily, in the embodiment that the plurality of placing holes 310 are arranged on the heating piece 300 at intervals, the bubbling assembly 500 can further comprise a flow dividing piece 520. The flow dividing piece 520 can be provided with an air inlet hole 521 and a plurality of air outlet holes 522. The air outlet holes 522 can be arranged one by one corresponding to the placing holes 310. The air inlet hole 521 can pass through the flow dividing piece 520. One end of the plurality of air outlet holes 522 can be respectively communicated to the middle part between the two ends of the air inlet hole 521. One end of the stop valve can be connected to the gas source three-way piece. The other end of the stop valve can be respectively connected to the two ends of the air inlet hole 521. The speed regulating valves 510 can be arranged one by one corresponding to the air outlet holes 522. The speed regulating valves 510 can be connected one by one between the other end of the plurality of air outlet holes 522 and the air inlet 420. In this way, after the gas passes through the stop valve, it can enter the flow dividing piece 520 from the two ends of the air inlet hole 521 respectively, and then flow out through the plurality of air outlet holes 522 respectively. The gas passing through the air outlet holes 522 can pass through the corresponding speed regulating valves 510 and the air inlet 420 respectively, so as to enter the to-be-heated piece 600. In this way, each speed regulating valve 510 can independently adjust the flow on the gas path where it is located, so as to make the air inlet amounts of different to-be-heated pieces 600 the same or different to meet different needs. Moreover, since the gas enters through the two ends of the air inlet hole 521 and then flows out through the plurality of air outlet holes 522 respectively, the gas can relatively uniformly flow to each air outlet hole 522, thereby avoiding the problem that the gas passing through the downstream air outlet hole 522 is too little.

[0044] Exemplarily, the bubbling assembly 500 can further comprise a three-way piece 531 and a pair of air inlet pipes 532. One end of the three-way piece 531 can be connected to the stop valve. The other two ends of the three-way piece 531 can be connected one by one to the two ends of the air inlet hole 521 through the pair of air inlet pipes 532. The bubbling assembly 500 can further comprise an air outlet pipe 533. The air outlet pipe 533 can be connected one by one between the air outlet holes 522 and the air inlet 420. The speed regulating valves 510 can be arranged on the corresponding air outlet pipes 533.

[0045] In the description of the utility model, it is understood that the orientation words such as "front", "back", "up", "down", "left", "right", "transverse", "vertical", "vertical", "horizontal" and "top", "bottom" and the like indicated orientation or position relationship is usually based on the orientation or position relationship shown in the drawing, just for the convenience of describing the utility model and simplifying the description, in the case where no opposite statement is made, these orientation words do not indicate and imply that the indicated device or element must have a particular orientation or be constructed and operated in a particular orientation, therefore it can not be understood as the limitation of the protection scope of the utility model;The orientation words "in" and "out" refer to the inside and outside relative to the outline of each component.

[0046] For purposes of the description hereinafter, the terms "upper", "lower", "right", "left", "rear", "front", "vertical" and "horizontal" as can be perceived herein relative to the accompanying drawings refer to the orientation of the components being described. However, it is to be understood that the exemplary embodiments described herein can assume different orientations, except where expressly specified to the contrary. It is to be understood that the exemplary embodiments described herein can assume different orientations, except where expressly specified to the contrary. Thus, all devices shown in the figures are illustrative based upon the exemplary embodiments (and / or other adaptations of the exemplary embodiments) and are based on the application as claimed.

[0047] It is to be understood that the terms "first", "second", and the like, herein do not necessarily denote any ordinal, chronological or spatial relationship. It is to be understood that the terms "first", "second", and the like, herein do not necessarily denote any ordinal, chronological or spatial relationship. Moreover, it is to be understood that the terms "comprise", "comprising", "include", and / or "including", when used in this specification, specify the presence of stated features, steps, operations, components, elements, and / or groups thereof, but do not preclude the presence or addition of one or more other features, steps, operations, components, elements, and / or groups thereof.

[0048] It is to be understood that the terms "first", "second", and the like, herein do not necessarily denote any ordinal, chronological or spatial relationship. It is to be understood that the terms "first", "second", and the like, herein do not necessarily denote any ordinal, chronological or spatial relationship. Moreover, it is to be understood that the terms "comprise", "comprising", "include", and / or "including", when used in this specification, specify the presence of stated features, steps, operations, components, elements, and / or groups thereof, but do not preclude the presence or addition of one or more other features, steps, operations, components, elements, and / or groups thereof.

[0049] The utility model has carried on the explanation through the above embodiment, but should understand, the above embodiment is only for example and the purpose of explanation, but not the intention of the utility model is limited in the range of described embodiment. In addition, the skilled in the art can understand that the utility model is not limited to the above embodiment, according to the teaching of the utility model, more kinds of variations and modifications can also be made, and these variations and modifications all fall within the scope of the utility model claimed. The protection scope of the utility model is defined by the attached claims and its equivalent scope.

Claims

1. A heating device, characterized in that, include: Support plate; A heating element is disposed on a support plate, and the heating element is provided with a placement hole and a heating circulation channel surrounding the placement hole, the placement hole being used for inserting the element to be heated; as well as A connector is disposed on a support plate and located below the placement hole, the connector being used for detachable connection with the element to be heated inserted into the placement hole.

2. The heating device as described in claim 1, characterized in that, An observation hole is provided on the front side of the heating element, and the observation hole is connected to the placement hole.

3. The heating device as described in claim 2, characterized in that, The observation hole is located below the heating circulation channel.

4. The heating device as described in claim 1, characterized in that, The heating element has a plurality of placement holes spaced apart, and the connectors are located below the plurality of placement holes in a corresponding manner. The heating circulation channel surrounds the plurality of placement holes.

5. The heating device as described in claim 1, characterized in that, The connector is provided with a liquid inlet and an air inlet that connect to the component to be heated.

6. The heating device as described in claim 5, characterized in that, Along the extension direction of the connector, the liquid inlet and the air inlet are completely offset.

7. The heating device as described in claim 5, characterized in that, The heating device further includes a bubbling assembly disposed on one side of the heating element and located below the connector, the bubbling assembly being used to blow gas into the element to be heated through the air inlet.

8. The heating device as described in claim 7, characterized in that, The bubbling assembly includes a gas source triplet, a shut-off valve, and a speed control valve, which are connected in sequence along the gas flow direction.

9. The heating device as described in claim 8, characterized in that, The heating element is provided with a plurality of placement holes at intervals. The connecting parts are located below the plurality of placement holes in a corresponding manner. The bubbling assembly also includes a flow divider. The flow divider is provided with an air inlet and a plurality of air outlets. The air inlet passes through the flow divider. One end of the shut-off valve is connected to the air source triplet, and the other end is connected to both ends of the air inlet. One end of each of the plurality of air outlets is connected to the middle between the two ends of the air inlet. The speed regulating valve is connected between the other end of each of the plurality of air outlets and the air inlet in a corresponding manner.

10. A polypeptide synthesis apparatus, characterized in that, Includes the heating device as described in any one of claims 1-9.

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